Quaternary heteroatom containing compounds

ABSTRACT

The invention provides heterocyclic compounds with quaternary centers and methods of preparing compounds. Methods include the method for the preparation of a compound of Formula (II): 
     
       
         
         
             
             
         
       
     
     comprising treating a compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     with a transition metal catalyst and under alkylation conditions as valence and stability permit.

CROSS REFERENCE TO RELATED APPLICATION

This application is a Continuation-in-Part of U.S. application Ser. No.13/531,485, filed Jun. 22, 2012, which claims priority to and thebenefit of U.S. Provisional Application Ser. No. 61/501,054, filed onJun. 24, 2011, the entire contents of which are incorporated herein byreference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grant No. GM080269awarded by the National Institutes of Health. The government has certainrights in the invention.

TECHNICAL FIELD

The disclosure relates to quaternary nitrogen compounds useful asbuilding blocks in the synthesis of pharmaceuticals and other compounds.

BACKGROUND

Nitrogen-containing heterocycles are prevalent in numerous biologicallyactive products that are the bases and templates for countlesspharmaceuticals and other compounds used in many disciplines, includingmedicinal chemistry. A small sampling of some these compounds includeaspidospermidine, fawcettimine, vinblastine, manzamine A, ethosuximide,aminoglutethimide and doxapram, depicted below.

Typically only one enantiomer of a compound exhibits biologicalactivity, while the other enantiomer generally exhibits no activity, orsubstantially reduced activity. In addition, different stereoisomers ofa compound often exhibit differences in biological activity. As such, astereoselective and enantioselective synthesis of the target compoundcould theoretically produce pharmaceuticals or compounds with greaterbiological activity, and therefore, greater medicinal value. However,stereoselective and enantioselective syntheses of these types ofcompounds have proven very difficult. Indeed, most syntheses reported todate yield racemic mixtures of the various compounds. While somestereoselective methods for the synthesis of certain nitrogen containingheterocycles and their cyclic amine derivatives are known, only a sparsenumber of enantioselective methods exist. Additionally, most of thesestereoselective methods use chiral auxiliary chemistry specific to theoxindole lactam nucleus or cyclic imides, both of which require enolatestabilization, thereby limiting the scope of each transformation.

SUMMARY

The invention provides heterocyclic compounds with quaternary centersand methods for preparing compounds with quaternary centers. Theinvention further provides methods for preparing compounds withquaternary centers. Specifically, the invention provides a method forthe preparation of a compound of Formula (II):

comprising treating a compound of Formula (I):

with a transition metal catalyst under alkylation conditions, wherein,as valence and stability permit,

ring B represents an optionally substituted heterocycle;

X is a heteroatom;

R¹ is selected from optionally substituted alkyl, alkenyl, alkynyl,carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;

R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected ateach occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl.

The invention further provides compounds represented by Formulas (I) and(II).

The present invention further provides a method of preparation of acompound of Formula (IV):

comprising treating a compound of Formula (III):

with a transition metal catalyst under alkylation conditions, wherein,as valence and stability permit,

X is selected from —NR⁶— and —O—;

Z is selected from —C(O)—and —CR⁷R⁷—;

A is independently selected at each occurrence from —CR⁸R⁸— and —NR⁹—;

W is absent or selected from —O—, —NR¹⁰—, and —CR¹¹R¹¹—;

R¹ is selected from optionally substituted alkyl, alkenyl, alkynyl,carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;

R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected ateach occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl;

R⁷, R⁸, and R¹¹ are independently selected at each occurrence fromhydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl,thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl;

-   -   wherein R⁷ and R⁸ may combine with the carbons to which they are        bound to form an optionally substituted 3-8-membered ring, R⁸        and R¹¹ may combine with the carbons to which they are bound to        form an optionally substituted 3-8-membered ring, and when n is        2 or 3, R⁸ attached to one carbon may combine with R⁸ attached        to another carbon to combine with the carbons to which they are        bound to form a 3-8-membered ring;

R⁶, R⁹ and R¹⁰ are independently selected at each occurrence fromhydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl,aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy,sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide;and

n is 0-3.

The invention also comprises compounds represented by Formula (V):

or a tautomer and/or a salt thereof, wherein:

X is selected from —NR⁶— and —O—;

Z is selected from —C(O)—and —CR⁷R⁷—;

A is independently selected at each occurrence from —CR⁸R⁸— and —NR⁹—;

W is absent or selected from —O—, —NR¹⁰—, and —CR¹¹R¹¹—;

R¹ is selected from optionally substituted alkyl, alkenyl, alkynyl,carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;

R¹², R¹³, R¹⁴ and R¹⁵ are independently selected at each occurrence fromhydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano,carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl,alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide,thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl,heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, andheterocyclylalkyl;

R⁷, R⁸, and R¹¹ are independently selected at each occurrence fromhydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl,thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl;

-   -   wherein R⁷ and R⁸ may combine with the carbons to which they are        bound to form an optionally substituted 3-8-membered ring, R⁸        and R¹¹ may combine with the carbons to which they are bound to        form an optionally substituted 3-8-membered ring, and when n is        2 or 3, R⁸ attached to one carbon may combine with R⁸ attached        to another carbon to combine with the carbons to which they are        bound to form a 3-8-membered ring;

R⁶, R⁹ and R¹⁰ are independently selected at each occurrence fromhydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl,aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy,sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide;and

n is 0-3.

The invention further comprises compounds represented by Formula (VI):

or a tautomer and/or a salt thereof, wherein:

X is selected from —NR⁶— and —O—;

Z is selected from —C(O)—and —CR⁷R⁷—;

A is independently selected at each occurrence from —CR⁸R⁸— and —NR⁹—;

W is absent or selected from —O—, —NR¹⁰—, and —CR¹¹R¹¹—;

R¹ is selected from optionally substituted alkyl, alkenyl, alkynyl,carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;

R², R³, R⁴ and R⁵ are independently selected at each occurrence fromhydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano,carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl,alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide,thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl,heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, andheterocyclylalkyl;

R⁷, R⁸, and R¹¹ are independently selected at each occurrence fromhydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl,thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl;

-   -   wherein R⁷ and R⁸ may combine with the carbons to which they are        bound to form an optionally substituted 3-8-membered ring, R⁸        and R¹¹ may combine with the carbons to which they are bound to        form an optionally substituted 3-8-membered ring, and when n is        2 or 3, R⁸ attached to one carbon may combine with R⁸ attached        to another carbon to combine with the carbons to which they are        bound to form a 3-8-membered ring;

R⁶, R⁹ and R¹⁰ are independently selected at each occurrence fromhydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl,aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy,sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide;and

n is 0-3.

In embodiments of the present invention, a compound is represented byFormula A, Formula A(ii), Formula D or Formula D(i).

In Formula A, A(ii), D and D(i), z is 0 or 1; Q is a heteroatom; each ofR1 through R11 and Ra through Rf is independently hydrogen, asubstituted or unsubstituted hydrocarbyl group, a substituted orunsubstituted heteroatom containing hydrocarbyl group, or a functionalgroup; each of d, e and f is independently an integer of 0 or greater;each of A, B and D is independently a carbon atom or a heteroatom; andtwo or more groups selected from R1 though R11, Ra through Rf and Yoptionally combine to form a ring. In some embodiments, R8 and R9combine to form a carbonyl group. In some embodiments, R2 and Y combineto form a ring with Q, and the ring may be saturated or may include atleast one double bond. In some embodiments, Q is N or O. When Q is N, R1may be an amine protecting group. In some embodiments, however, R1 maybe H or OH. For example, in some embodiments, z is 0 and R1 is either Hor OH.

In some exemplary embodiments, the compound of Formula A may be acompound represented by Formula C.

In Formula C, z is 0 or 1; each of d, e and f is independently aninteger of 0 or greater; Q1 is a heteroatom; and each of A, B and D isindependently a heteroatom or a carbon atom. In some embodiments, R1 maybe H or OH. For example, in some embodiments, z is 0 and R1 is either Hor OH. In Formula C, R8 and R9 may optionally combine to form a carbonylgroup such that the compound of Formula C is represented by FormulaC(i).

In Formulae C and C(i), R1 and one Ra may combine to form a double bond,or one Rb and one Rc may combine to form a double bond, or one Rd andone Re may combine to form a double bond. In some embodiments, inFormulae C and C(i), one Ra and one Rb may combine to form a carbonylgroup, or one Rc and one Rd may combine to form a carbonyl group, or oneRe and one Rf may combine to form a carbonyl group. Also, in someembodiments, R1 is H or OH. In some embodiments, the compound of FormulaA, A(ii), D or D(i) is racemic, i.e., the compound includes a generallyequimolar mixture of the (+) and (−) enantiomers of the compound. Forexample, in some embodiments, e.g., those in which z is 1, the compoundis racemic. However, in some other embodiments, the compound of FormulaA, A(ii), D or D(i) is enantioenriched, i.e., the compound includes moreof one enantiomer than the other. For example, in some embodiments,e.g., in which z is 0, the compound may be an enantioenriched compoundin which the compound includes one of the (+) or the (−) enantiomer inan enantiomeric excess of greater than 50%, for example greater than60%, or greater than 70%, or greater than 80%, or greater than 90%.

According to some embodiments of the present invention, a method ofmaking an enantioenriched heteroatom containing compound includessubjecting the compound of claim 1 to palladium catalyzeddecarboxylative alkylation using an electron poor ligand, apalladium-based catalyst, and a solvent. The electron poor ligand may bea ligand including an electron poor moiety selected from fluorine atoms,partially or fully fluorinated hydrocarbyl groups, partially or fullyfluorinated heteroatom containing hydrocarbyl groups, NO₂ groups andSO₂R groups, wherein R is hydrogen, a substituted or unsubstitutedhydrocarbyl group, a substituted or unsubstituted heteroatom containinghydrocarbyl group, or a functional group. For example, the electron poorligand may be a R′—PHOX ligand, where R′ is selected from (CF₃)₃ groups,partially or fully fluorinated hydrocarbyl groups, partially or fullyfluorinated heteroatom containing hydrocarbyl groups, NO₂ groups andSO₂R groups, wherein R is hydrogen, a substituted or unsubstitutedhydrocarbyl group, a substituted or unsubstituted heteroatom containinghydrocarbyl group, or a functional group.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and advantages of the present invention will bebetter understood by reference to the following detailed descriptionwhen considered in conjunction with the following drawing, in which:

FIG. 1 is a graph comparing the enantiomeric excess of differentcompounds prepared via a palladium catalyzed decarboxylative alkylationprocess according to embodiments of the present invention.

DETAILED DESCRIPTION I. Definitions

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbyl-C(O)—, such as alkyl-C(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbyl-C(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbyl-C(O)O—, preferably alkyl-C(O)O—.

The term “alkoxy” refers to an alkyl group having an oxygen attachedthereto. Representative alkoxy groups include methoxy, ethoxy, propoxy,tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, andcycloalkyl-substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone, e.g., C₁-C₃₀ for straight chains, C₃-C₃₀ for branchedchains, and more preferably 20 or fewer, e.g., C₁-C₃, C₁-C₆, C₁-C₉,C₁-C₁₂, C₁-C₁₅ and C₁-C₁₈. Likewise, preferred cycloalkyls have from3-10 carbon atoms in their ring structure, and more preferably have 5, 6or 7 carbons in the ring structure.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing one or morehydrogen atoms on one or more carbons of the hydrocarbon backbone. Suchsubstituents can include, for example, a halogen, a hydroxyl, a carbonyl(such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), athiocarbonyl (such as a thioester, a thioacetate, or a thioformate), analkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat the moieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), —CF₃, —CN andthe like. Exemplary substituted alkyls are described below. Cycloalkylscan be further substituted with alkyls, alkenyls, alkoxys, alkylthios,aminoalkyls, carbonyl-substituted alkyls, —CF₃, —CN, and the like.

The term “C_(x-y)” or “C_(x) to C_(y)-alkyl” when used in conjunctionwith a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl,or alkoxy is meant to include groups that contain from x to y carbons inthe chain. For example, the term “C_(x) to C_(y)-alkyl” refers tosubstituted or unsubstituted saturated hydrocarbon groups, includingstraight-chain alkyl and branched-chain alkyl groups that contain from xto y carbons in the chain, including haloalkyl groups such astrifluoromethyl and 2,2,2-trifluoroethyl, etc. The terms “C_(x) toC_(y)-alkenyl” and “C_(x) to C_(y)-alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively. Within a range of C_(x-y),subranges are also generally envisioned. For example, for the range C₁to C₁₅-alkyl, ranges falling within this range such as C₁ to C₂-alkyland C₂ to C₈- alkyl are also included.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkyl-S—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein R²⁰ and R²¹ each independently represent a hydrogen orhydrocarbyl group, or R²⁰ and R²¹ taken together with the N atom towhich they are attached complete a heterocycle having from 4 to 8 atomsin the ring structure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein R²⁰, R²¹, and R²² each independently represent a hydrogen or ahydrocarbyl group, or R²⁰ and R²¹ taken together with the N atom towhich they are attached complete a heterocycle having from 4 to 8 atomsin the ring structure. The terms “amine” and “amino” are intended toinclude amine groups that may be protected by a protecting group such asa carbobenzyloxy group (Cbz), a tert-butyloxycarbonyl group (BOC), a9-fluorenylmethyloxycarbonyl group (FMOC), an acetyl group, a benzoylgroup, a benzyl group, and a tosyl group.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which one or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “carbamate” is art-recognized and refers to a group

wherein R²⁰ and R²¹ independently represent hydrogen or a hydrocarbylgroup.

The terms “carbocycle”, “carbocyclyl”, and “carbocyclic”, as usedherein, refers to a non-aromatic saturated or unsaturated ring in whicheach atom of the ring is carbon. Preferably a carbocycle ring containsfrom 3 to 10 atoms, more preferably from 5 to 7 atoms.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R²⁰,wherein R²⁰ represents a hydrocarbyl group.

The term “carboxyl”, as used herein, refers to a group represented bythe formula -CO2H. The term “ester”, as used herein, refers to a group—C(O)OR²⁰ wherein R²⁰ represents a hydrocarbyl group such as an arylgroup.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The term “haloalkyl” as used herein includes from one halo substituentup to perhalo substitution. Exemplary haloalkyls includes —CFH₂, —CClH₂,—CBrH₂, —CF₂H, —CCl₂H, —CBr₂H, —CF₃, —CCl₃, —CBr₃, —CH₂CH₂F, —CH₂CH₂Cl ,—CH₂CH₂Br, —CH₂CHF₂, —CHFCH₃, —CHClCH₃ , —CHBrCH₃, —CF₂CHF₂, —CF₂CHCl₂,—CF₂CHBr₂, —CH(CF₃)₂, and —C(CF₃)₃. Perhaloalkyl, for example, includes—CF₃, —CCl₃, —CBr₃, —CF₂CF₃, —CCl₂CF₃ and —CBr₂CF₃.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 8-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl”, “heterocycle” and “heterocyclic” also include polycyclicring systems having two or more cyclic rings in which one or morecarbons are common to two adjoining rings wherein at least one of therings is heterocyclic, e.g., the other cyclic rings can be selected fromcycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/orheterocyclyl. Heterocyclyl groups include, for example, piperidine,piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to optionally substitutedalkyl, alkenyl, alkynyl, carbocycle and aryl and combinations thereof.

The term “hydroxyl” or “hydroxy”, as used herein, refers to an OH group.The term “hyrdoxy” or “hydroxyl” is intended to include groups that maybe protected by a protecting group such as a TBDMS or TIPS protectinggroups.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group. The term “hydroxyalkyl” is intended toinclude hydroxyl groups that may be protected by a protecting group suchas a TBDMS or TIPS protecting groups.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

A “protecting group” as used herein has the meaning ascribed in thefield. A protecting group is a group that is covalently bound to afunctional group in order to maintain chemoselectivity in a subsequentchemical reaction. Protecting groups for nitrogen atoms include “amineprotecting groups” and “amide protecting groups”. Protecting groups forhydroxyl groups include “hydroxyl protecting groups”. The need forprotection and deprotection, and the selection of appropriate protectinggroups can be readily determined by one skilled in the art. Thechemistry of protecting groups can be found, for example, in Greene andWuts, Protective Groups in Organic Synthesis, 4th. Ed., Wiley & Sons,2007, which is incorporated herein by reference in its entirety. Thoseof ordinary skill in the art would readily understand what is meant by“amine protecting group” and “amide protecting groups”, however, somenonlimiting examples of nitrogen protecting groups include carboxybenzyl(Cbz) groups, p-methoxybenzyl carbonyl (Moz or MeOZ) groups,tent-butyloxycarbonyl (BOC) groups, fluorenylmethyloxycarbonyl (FMOC)groups, acetyl (Ac) groups, benzoyl (Bz) groups, benzyl (Bn) groups,carbamate groups, p-methoxybenzyl (PMB) groups, dimethoxybenzyl (DMPM)groups, p-methoxyphenyl (PMP) groups, tosyl (Ts) groups, sulfonamide(Nosyl & Nps) groups, methoxybenzoyl groups (OMe-Bz), and fluorobenzoylgroups (F-Bz). For example, in some embodiments, the amine protectinggroup is selected from tosyl groups (Ts), butyloxycarbonyl groups (BOC),carbobenzyloxy groups (Cbz), fluoreneylmethyloxycarbonyl groups (FMOC),acetyl groups (Ac), methoxybenzoyl groups (OMe-Bz), and fluorobenzoylgroups (F-Bz). Those of ordinary skill in the art would readilyunderstand what is meant by “hydroxyl protecting group”, however, somenonlimiting examples of hydroxyl protecting groups include an acetyl(Ac) group, a benzoyl (Bz) group, a benzyl (Bn) group, a β-methoxyethoxymethyl (MEM) group, a methoxy methyl (MOM) group, a silyl group such asa trimethylsilyl (TMS) group, a tert-butyldimethylsilyl (TBDMS) group,and a triisopropylsilyl (TIPS) group.

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes, except for whereotherwise provided, the implicit proviso that such substitution is inaccordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound,e.g., which does not spontaneously undergo transformation such as byrearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents oforganic compounds. In a broad aspect, the permissible substituentsinclude acyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisinvention, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms.Substituents can include any substituents described herein, for example,a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the moietiessubstituted at a position can themselves be substituted, if appropriate.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R²⁰ and R²¹ independently represents hydrogen or hydrocarbyl.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R²⁰, wherein R²⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R²⁰,wherein R²⁰ represents a hydrocarbyl.

The term “tautomer” as used herein is art-recognized and refers to theformal migration of a hydrogen atom, accompanied by a switch of a singlebond and adjacent double bond. When used herein to describe a compoundor genus of compounds, tautomer includes any portion of a compound orthe entire compound such as a single substituent of a compound, multiplesubstituents of a compound or, for example, the entire compound. Forexample, the tautomer of a compound that includes a hydroxyalkene (A) isthe aldehyde (B):

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR²⁰ or—SC(O)R²⁰ wherein R²⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R²⁰ and R²¹ independently represent hydrogen or a hydrocarbyl.

II. Description of the Invention

Nitrogen-containing heterocycles are ubiquitous in natural products,pharmaceuticals, and materials science. Given the abundance of theseheterocycles in nature, pharmacology, and materials science,stereoselective methods for the synthesis of 3,3-disubstitutedpyrrolidinones, piperidinones, and caprolactams, in addition to theircorresponding amines, would, in theory, be valuable for the preparationof a wide array of important structures in these areas of research. Thegeneral formulae for such disubstituted pyrrolidinones, piperidinones,and caprolactams are depicted below.

A small sample of the products these disubstituted pyrrolidinones,piperidinones and caprolactams could theoretically be used to prepareincludes those depicted below.

However, as can be seen from the small sample depicted above, many ofthe target compounds include quaternary centers, e.g., C(a)-quaternarycenters. Unfortunately, a paucity of enantioselective lactam synthesesleading to such C(a)-quaternary centers is known. Indeed, most knownmethods rely on chiral auxiliary chemistry, and although a few catalyticexamples exist, they are specific to the oxindole lactam nucleus,a-carbonyl stabilized enolates, or cyclic imides. Importantly, enolatestabilization is critical for success in these catalytic systems,thereby limiting the scope of each transformation. To date, there are noexamples of catalytic asymmetric alkylations of simple piperidinone,pyrrolidinone, and caprolactam scaffolds (or other nitrogen containingcompounds, e.g., acyclic compounds) for the formation of C(α)-quaternaryor C(α)-tetrasubstituted tertiary centers.

Transition metal-catalyzed allylic alkylation is a key method for theenantioselective preparation of chiral substances and ranks among thebest general techniques for the catalytic alkylation of prochiralenolates. Given the importance of α-quaternary lactams (discussedabove), embodiments of the present invention are directed to a generalmethod for catalytic asymmetric α-alkylation of cyclic and acyclicquaternary heteroatom containing compounds (including nitrogencontaining compounds, e.g., lactams, and their structurally analogousoxygen containing compounds, e.g., lactones). Over the past severalyears, methods for the synthesis of α-quaternary ketones have beenreported, and the use of these methods has been demonstrated in a numberof complex molecule syntheses. See Mohr, et al., “Deracemization ofquaternary stereocenters by Pd-catalyzed enantioconvergentdecarboxylative allylation of racemic β-ketoesters,” Angew. Chem., Int.Ed. 44, 6924-6927 (2005); Seto, et al., “Catalytic enantioselectivealkylation of substituted dioxanone enol ethers: ready access toC(a)-tetrasubstituted hydroxyketones, acids, and esters,” Angew. Chem.Int. Ed. 47, 6873-6876 (2008); Streuff, et al., “A Palladium-catalysedenolate alkylation cascade for the formation of adjacent quaternary andtertiary stereocenters,” Nature Chem. 2, 192-196 (2010); McFadden, etal., “The catalytic enantioselective, protecting group-free totalsynthesis of (+)-dichroanone,” J. Am. Chem. Soc. 128, 7738-7739 (2006);White, et al., “The catalytic asymmetric total synthesis of elatol,” J.Am. Chem. Soc. 130, 810-811 (2008); Enquist, et al., “The totalsynthesis of (−)-cyanthiwigin F via double catalytic enantioselectivealkylation,” Nature 453, 1228-1231 (2008); Day, et al., “The catalyticenantioselective total synthesis of (+)-liphagal,” Angew. Chem. Int. Ed.50, in press (2011), the entire content of all of which are incorporatedherein by reference. Related allylic alkylation methods have also beendeveloped. See Trost, et al., “Regio- and Enantioselective Pd-CatalyzedAllylic Alkylation of Ketones through Allyl Enol Carbonates,” J. Am.Chem. Soc. 127,2846-2847 (2005); Trost, et al., “Palladium-CatalyzedAsymmetric Allylic a-Alkylation of Acyclic Ketones,” J. Am. Chem. Soc.127,17180-17181 (2005); Trost, et al., “Asymmetric Allylic Alkylation ofCyclic Vinylogous Esters and Thioesters by Pd-Catalyzed Decarboxylationof Enol Carbonate and β-Ketoester Substrates,” Angew. Chem., Int. Ed.45, 3109-3112 (2006); Trost, et al., “Enantioselective Synthesis ofα-Tertiary Hydroxyaldehydes by Palladium-Catalyzed Asymmetric AllylicAlkylation of Enolates.” J. Am. Chem. Soc. 129, 282-283 (2007); Trost,et al., “Palladium-Catalyzed Decarboxylative Asymmetric AllylicAlkylation of Enol Carbonates,” J. Am. Chem. Soc. 131, 18343-18357(2009); Nakamura, et al., “Synthesis of Chiral a-Fluoroketones throughCatalytic Enantioselective Decarboxylation,” Angew. Chem., Int. Ed. 44,7248-7251 (2005); Burger, et al., “Catalytic Asymmetric Synthesis ofCyclic α-Allylated a-Fluoroketones,” Synlett 2824-2826 (2006); Belanger,et al., “Enantioselective Pd-Catalyzed Allylation Reaction ofFluorinated Silyl Enol Ethers,” J. Am. Chem. Soc. 129, 1034-1035 (2007);Schulz, et al., “Palladium-Catalyzed Synthesis of SubstitutedCycloheptane-1,4-diones by an Asymmetric Ring-Expanding Allylation(AREA),” Angew. Chem., Int. Ed. 46, 3966-3970 (2007), the entire contentof all of which are incorporated herein by reference.

According to embodiments of the present invention, a wide range ofstructurally-diverse, functionalized heteroatom containing compounds(e.g., nitrogen containing lactams and oxygen containing lactones) areprepared by a stereoselective method including palladium-catalyzedenantioselective enolate alkylation. This chemistry is important to thesynthesis of bioactive alkaloids, and the transformation is useful forthe construction of novel building blocks for medicinal and polymerchemistry. Indeed, in some embodiments of the present invention, thesenovel building blocks include heteroatom containing compounds useful asprecursors to (or reactants leading to the preparation of) numerousbiologically active and important natural and pharmaceutical products.While embodiments of the present invention are directed to the novelbuilding blocks achieved from the transition-metal catalyzed allylicalkylation reaction, other embodiments of the present invention aredirected to novel heteroatom containing substrates used in thetransition-metal catalyzed allylic alkylation reaction to form thebuilding blocks. Indeed, in some embodiments of the present invention, amethod of making a building block compound comprises reacting asubstrate compound with a ligand in the presence of a palladium-basedcatalyst and a solvent. The palladium-based catalysts, ligands andsolvents useful in this reaction are described in more detail below inthe section entitled “Palladium-Catalyzed Decarboxylative Alkylation.”The substrates used in the reaction, and the building block compoundsmade from the reaction are described here, and in the below sectionsentitled “Heteroatom Containing Substrate Compounds” and “HeteroatomContaining Building Block Compounds.”

III. Compounds and Methods of the Invention

The present invention provides a method for the preparation of acompound of Formula (II):

comprising treating a compound of Formula (I):

with a transition metal catalyst and under alkylation conditions,wherein, as valence and stability permit,

ring B represents an optionally substituted heterocycle;

X is a heteroatom;

R¹ is selected from optionally substituted alkyl, alkenyl, alkynyl,carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;

R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected ateach occurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl,cyano, carboxyl, sulfate, alkoxy, alkylamino, alkylthio, hydroxyalkyl,alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide,thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl,heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, andheterocyclylalkyl.

In addition to methods for preparing compounds of Fomula (II), theinvention further discloses compounds represented by Formula (I) andFormula (II). The following discussion of Ring B as well as variables X,R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ refers to both the method ofpreparing a compound of Formula (II) from a compound of Formula (I) andthe compounds of Formula (I) and (II).

Ring B of the compound of Formula (I) or (II) may contain one or moreheteroatoms selected from O, N, S, P, B, or Si. In certain embodiments,X of ring B is nitrogen or oxygen wherein nitrogen is optionallysubstituted. In addition to X, ring B may contain one or more additionalheteroatoms such as a nitrogen or an oxygen. Ring B may represent asubstituted 4-8 membered ring or preferably a substituted 5-7 memberedring. In particular, ring B may represent an optionally substituted5-7-membered lactam ring. Alternatively, ring B may represent anoptionally substituted 5-7 membered lactone ring.

As valence and stability permit, ring B may be saturated or containunsaturation with, for example, one or more multiple bonds. Substituentson ring B may be selected from at least: a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, an arylcarbonyl, anaryloxycarbonyl, an aralkoxycarbonyl, a formyl, or an acyl), athiocarbonyl (such as a thioester, a thioacetate, or a thioformate), analkoxyl, a phosphoryl, a phosphate, an aryloxy, an aralkyloxy, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, asulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, anaralkyl, or an aromatic or heteroaromatic moiety. In addition, one ormore of the substituents on ring B may also be substituted by one ormore substituents.

While not wishing to be bound by a particular mechanism, the reactionsdisclosed herein may proceed by directly linking the carbon bearing R²to the carbon bearing R¹. Accordingly, in some embodiments, the carbonbearing the R² groups in a compound of Formula (I) may be the carbonbearing the R¹² groups in a compound of Formula (II), and thus R¹² inthe product is the same as R² in the reactant. Similarly, in theseembodiments, the carbon bearing R⁴ and R⁵ in a compound of Formula (I)may be the carbon bearing R¹⁴ and R¹⁵ groups in a compound of Formula(II) (so that R¹⁴ in the product is the same as R⁴ in the reactant, andR¹⁵ in the product is the same as R⁵ in the reactant) and the carbonbearing R³ in a compound of Formula (I) may be the carbon bearing R¹³ ina compound of Formula (II) (making R¹³ in the product the same as R³ inthe reactant).

Alternatively, the reactions disclosed herein may proceed through anallylic rearrangement of the allyl ester. In-such embodiments, thecarbon bearing the R² groups in a compound of Formula (I) may be thecarbon bearing the R¹⁴ and R¹⁵ groups in a compound of Formula (II)(meaning that R¹⁴ and R¹⁵ in the product are the same as the two R²groups in the reactant). Similarly, in these embodiments, the carbonbearing R⁴ and R⁵ in a compound of Formula (I) may be the carbon bearingR¹² groups in a compound of Formula (II) (meaning that the two R² groupsin the product are the same as R⁴ and R⁵ in the reactant) and the carbonbearing R³ in a compound of Formula (I) may be the carbon bearing R¹³ ina compound of Formula (II) (such that R¹³ in the product is the same asR³ in the reactant).

In preferred embodiments, wherein R², R⁴, R⁵, R¹², R¹⁴, and R¹⁵ are allhydrogen, the product is the same regardless of which mechanism applies,and regardless of the presence or absence of a non-hydrogen substituentat R³ and/or R¹³. In other embodiments, at least one of R², R⁴, R⁵, R¹²,R¹⁴, and R¹⁵ is a non-hydrogen substituent.

The present invention also provides a method of preparation of acompound of Formula (IV):

comprising treating a compound of Formula (III):

with a transition metal catalyst and under alkylation conditions,wherein, as valence and stability permit,

X is selected from —NR⁶— and —O—;

Z is selected from —C(O)—and —CR⁷R⁷—;

A is independently selected at each occurrence from —CR⁸R⁸— and —NR⁹—;

W is absent or selected from —O—, —NR¹⁰—, and —CR¹¹R¹¹—;

R¹ is selected from optionally substituted alkyl, alkenyl, alkynyl,carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;

R², R³, R⁴, R⁵, R¹², R¹⁴, and R¹⁵ are independently selected at eachoccurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl,cyano, carboxyl, sulfate, alkoxy, alkylamino, alkylthio, hydroxyalkyl,alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide,thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl,heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, andheterocyclylalkyl;

R⁷, R⁸, and R¹¹ are independently selected at each occurrence fromhydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl,thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl;

-   -   wherein R⁷ and R⁸ may combine with the carbons to which they are        bound to form an optionally substituted 3-8-membered ring; R⁸        and R¹¹ may combine with the carbons to which they are bound to        form an optionally substituted 3-8-membered ring; and when n is        2 or 3, R⁸ attached to one carbon may combine with R⁸ attached        to another carbon to combine with the carbons to which they are        bound to form a 3-8-membered ring;

R⁶, R⁹ and R¹⁰ are independently selected at each occurrence fromhydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl,aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy,sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide;and

n is 0-3.

While not wishing to be bound by a particular mechanism, the reactionsdisclosed herein may proceed by directly linking the carbon bearing R²to the carbon bearing R¹. Accordingly, in some embodiments, the carbonbearing the R² groups in a compound of Formula (III) may be the carbonbearing the R¹² groups in a compound of Formula (IV), and thus R¹² inthe product is the same as R² in the reactant. Similarly, in theseembodiments, the carbon bearing R⁴ and R⁵ in a compound of Formula (III)may be the carbon bearing R¹⁴ and R¹⁵ groups in a compound of Formula(IV) (so that R¹⁴ in the product is the same as R⁴ in the reactant, andR¹⁵ in the product is the same as R⁵ in the reactant) and the carbonbearing R³ in a compound of Formula (III) may be the carbon bearing R¹³in a compound of Formula (IV) (making R¹³ in the product the same as R³in the reactant).

Alternatively, the reactions disclosed herein may proceed through anallylic rearrangement of the allyl ester. In -such embodiments, thecarbon bearing the R² groups in a compound of Formula (III) may be thecarbon bearing the R¹⁴ and R¹⁵ groups in a compound of Formula (IV)(meaning that R¹⁴ and R¹⁵ in the product are the same as the two R²groups in the reactant). Similarly, in these embodiments, the carbonbearing R⁴ and R⁵ in a compound of Formula (III) may be the carbonbearing R¹² groups in a compound of Formula (IV) (meaning that the twoR² groups in the product are the same as R⁴ and R⁵ in the reactant) andthe carbon bearing R³ in a compound of Formula (III) may be the carbonbearing R¹³ in a compound of Formula (IV) (such that R¹³ in the productis the same as R³ in the reactant). In preferred embodiments, whereinR², R⁴, R⁵, R¹², R¹⁴, and R¹⁵ are all hydrogen, the product is the sameregardless of which mechanism applies, and regardless of the presence orabsence of a non-hydrogen substituent at R³ and/or R¹³. In otherembodiments, at least one of R², R⁴, R⁵, R¹², R¹⁴, and R¹⁵ is anon-hydrogen substituent.

The invention also comprises compounds represented by Formula (V):

or a tautomer and/or a salt thereof, wherein:

X is selected from —NR⁶— and —O—;

Z is selected from —C(O)—and —CR⁷R⁷—;

A is independently selected at each occurrence from —CR⁸R⁸— and —NR⁹—;

W is absent or selected from —O—, —NR¹⁰—, and —CR¹¹R¹¹—;

R¹ is selected from optionally substituted alkyl, alkenyl, alkynyl,carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;

R¹², R¹³, R¹⁴ and R¹⁵ are independently selected at each occurrence fromhydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano,carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl,alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide,thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl,heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, andheterocyclylalkyl;

R⁷, R⁸, and R¹¹ are independently selected at each occurrence fromhydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl,thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl;

-   -   wherein R⁷ and R⁸ may combine with the carbons to which they are        bound to form an optionally substituted 3-8-membered ring; R⁸        and R¹¹ may combine with the carbons to which they are bound to        form an optionally substituted 3-8-membered ring; and when n is        2 or 3, R⁸ attached to one carbon may combine with R⁸ attached        to another carbon to combine with the carbons to which they are        bound to form a 3-8-membered ring;

R⁶, R⁹ and R¹⁰ are independently selected at each occurrence fromhydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl,aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy,sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide;and n is 0-3.

The invention also comprises compounds represented by Formula (VI):

or a tautomer and/or a salt thereof, wherein:

X is selected from —NR⁶— and —O—;

Z is selected from —C(O)—and —CR⁷R⁷—;

A is independently selected at each occurrence from —CR⁸R⁸— and —NR⁹—;

W is absent or selected from —O—, —NR¹⁰—, and —CR¹¹R¹¹—;

R¹ is selected from optionally substituted alkyl, alkenyl, alkynyl,carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;

R², R³, R⁴ and R⁵ are independently selected at each occurrence fromhydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl,sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl,alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide,thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl,heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, andheterocyclylalkyl;

R⁷, R⁸, and R¹¹ are independently selected at each occurrence fromhydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl,thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl;

-   -   wherein R⁷ and R⁸ may combine with the carbons to which they are        bound to form an optionally substituted 3-8-membered ring; R⁸        and R¹¹ may combine with the carbons to which they are bound to        form an optionally substituted 3-8-membered ring; and when n is        2 or 3, R⁸ attached to one carbon may combine with R⁸ attached        to another carbon to combine with the carbons to which they are        bound to form a 3-8-membered ring;

R⁶, R⁹ and R¹⁰ are independently selected at each occurrence fromhydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl,aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy,sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide;and

n is 0-3.

R¹ of a compound of Formula (I)-(VI) may be selected from halogen and anoptionally substituted group selected from alkyl, carbocyclyl,carbocyclylalkyl, cyanoalkyl, aralkyl, heteroaralkyl, hydroxyalkyl,haloalkyl, acylalkyl, alkoxycarbonylalkyl, and aryloxycarbonylalkyl. Inparticular, R¹ may be selected from halogen, alkyl, optionallysubstituted aralkyl, optionally substituted alkoxycarbonylalkyl,optionally substituted cyanoalkyl, and optionally substitutedhydroxyalkyl. In particular, R¹ may be selected from halogen andoptionally substituted alkyl, wherein alkyl is substituted by one ormore of: halogen, hydroxyl, cyano, alkoxy, aryloxy, alkylsilyloxy, aryl,alkyl-substituted aryl, haloalkyl-substited aryl, alkylthio,carbocyclyl, arylcarbonyl, aralkylcarbonyl, heteroaryl, aralkyloxy,heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, alkylsulfonyl, aryl sulfonyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, and amide.

When R¹ is optionally substituted alkyl in any of Formulas (I)-(VI),alkyl may be selected from optionally substituted C₁ to C₁₀-alkyl, suchas optionally substituted C₁ to C₅-alkyl. In particular, R¹ isoptionally substituted alkyl and alkyl is selected from optionallysubstituted C₁ to C₃-alkyl. When R¹ is halogen, R¹ may be selected fromchloro, bromo and fluoro. In certain embodiments, R¹ may be fluoro.

R² and R¹² of a compound of Formula (I)-(VI) may be independentlyselected at each occurrence from hydrogen, halogen, hydroxyl, haloalkyl,cyano, alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl. Inparticular, R² and R¹² may be selected at each occurrence from hydrogen,halogen, haloalkyl and hydroxyl. For example, R² and R¹² at eachoccurrence is hydrogen.

R³, R⁴, R⁵, R¹³, R¹⁴, and R¹⁵ of a compound of Formula (I)-(VI) may beindependently selected at each occurrence from hydrogen, halogen,haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, andaralkyloxy. In particular, R³, R⁴, R⁵, R¹³, R¹⁴, and R¹⁵ may beindependently selected at each occurrence from hydrogen, halogen,haloalkyl, cyano, alkyl, and alkoxy. For example, R³, R⁴, R⁵, R¹³, R¹⁴,and R¹⁵ may be independently selected at each occurrence from chloro,bromo, fluoro, and C₁ to C₅-alkyl wherein alkyl is optionallysubstituted with one or more halogens or hydroxyls.

Two of R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ of a compound of Formula(I)-(VI), may be taken together with the carbons to which they are boundto form a ring. For example, R³ and R⁴ may combine with the carbons towhich they are bound to form an optionally substituted 5-8-memberedring, R¹³ and R¹⁴ may combine with the carbons to which they are boundto form an optionally substituted 5-8-membered ring, R⁴ and R⁵ maycombine with the carbons to which they are bound to form a 3-8-memberedring, R¹⁴ and R¹⁵ may combine with the carbons to which they are boundto form a 3-8-membered ring, R² together with R³, R⁴ or R⁵ may combinewith the carbons to which they are bound to form a 5-8-membered ring,and R¹² together with R¹³, R¹⁴, or R¹⁵ may combine with the carbons towhich they are bound to form a 5-8-membered ring. A ring formed by anytwo of R², R³, R⁴ and R⁵ and any two of R¹², R¹³, R¹⁴ and R¹⁵ may beoptionally substituted with one or more substituents selected fromhalogen, hydroxyl, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide,amine.

R⁷, R⁸, and R¹¹ of a compound of Formula (III)-(VI) may be independentlyselected at each occurrence from hydrogen, halogen, hydroxyl, haloalkyl,cyano, alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl. Inparticular, R⁷, R⁸, and R¹¹ may be independently selected at eachoccurrence from hydrogen, halogen, haloalkyl and hydroxyl. In particularembodiments when two of R⁷, R⁸, and R¹¹ combine with the atoms to whichthey are bound to form a ring, the ring may be substituted by one ormore of halogen, hydroxyl, haloalkyl, cyano, alkyl, alkoxy, alkylthio,amide, amine.

R⁶, R⁹, and R¹⁰ of a compound of Formula (III)-(VI) may be independentlyselected at each occurrence from hydrogen, hydroxyl, and an optionallysubstituted groups selected from alkyl, alkoxy, alkylthio, aryloxy,carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl, aralkyl,heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl,aralkylcarbonyl, acyloxy, alkyl sulfonyl, aryl sulfonyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, and amide. In certain embodiments,R⁶, R⁹, and R¹⁰ are independently selected from an optionallysubstituted amine or amide protecting group. In particular, R⁶, R⁹, andR¹⁰ may be independently selected at each occurrence from optionallysubstituted aralkyloxy, aralkoxycarbonyl, heteroaryloxy, acyl,arylcarbonyl, aralkylcarbonyl, arylsulfonyl, alkoxycarbonyl, andaryloxycarbonyl, wherein the substituents may be selected from one ormore of halogen, alkyl, alkoxy, haloalkyl, phenyl and hydroxyl.

For a compound of any of Formulas (III)-(VI), X may be —NR⁶—; Z may beselected from —C(O)— and —CR⁷R⁷—; A at each occurrence may be —CR⁸R⁸— ;W may be selected from —NR¹⁰— and —CR¹¹R¹¹—; and n may be 0-2. In suchembodiments, R¹ may be selected from halogen, alkyl, optionallysubstituted aralkyl, optionally substituted alkoxycarbonylalkyl,optionally substituted cyanoalkyl, and optionally substitutedhydroxyalkyl; R² and R¹² may be selected at each occurrence fromhydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl, alkoxy, alkylthio,amide, amine, and carbocyclyl; R³, R⁴, R⁵, R¹³, R¹⁴, and R¹⁵ may beindependently selected at each occurrence from hydrogen, halogen,haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, andaralkyloxy; R⁷, R⁸, and R¹¹ may be independently selected at eachoccurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl,alkoxy, alkylthio, amide, amine, and carbocyclyl; and R⁶ and R¹⁰ may beindependently selected at each occurrence from hydrogen, hydroxyl, andan optionally substituted groups selected from alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl,aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl,aralkylcarbonyl, acyloxy, alkyl sulfonyl, aryl sulfonyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, and amide.

For a compound of any of Formulas (III)-(VI), X may be —NR⁶—; Z may be—CR⁷R⁷—; A may be —CR⁸R⁸— ; W may be —NR¹⁰—; and n may be 1. Thecompound of Formula (IV) or (V) may be represented by the Formula (IVa):

and the compound of Formula (III) and (VI) may be represented by theFormula (Ma):

In such embodiments, R¹ may be selected from halogen, alkyl, optionallysubstituted aralkyl, optionally substituted alkoxycarbonylalkyl,optionally substituted cyanoalkyl, and optionally substitutedhydroxyalkyl; R² and R¹² may be independently selected at eachoccurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl,alkoxy, alkylthio, amide, amine, and carbocyclyl; R³, R⁴, R⁵, R¹³, R¹⁴,and R¹⁵ may be independently selected at each occurrence from hydrogen,halogen, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine,aryloxy, and aralkyloxy; R⁷ and R⁸ may be independently selected at eachoccurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl,alkoxy, alkylthio, amide, amine, and carbocyclyl; and R⁶ and R¹⁰ may beindependently selected at each occurrence from an amine or amideprotecting group, hydrogen, hydroxyl, and an optionally substitutedgroups selected from alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl,aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl, aralkyl, heteroaralkyl,aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy,alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, and amide.

In certain embodiments, for a compound of any of Formulas (III)-(VI), Xis —NR⁶—; Z is selected from —C(O)—and —CR⁷R⁷—; A at each occurrence is—CR⁸R⁸—; W is —CR¹¹R¹¹—, and n is 0-2. In such embodiments, R¹ may beselected from halogen, alkyl, optionally substituted aralkyl, optionallysubstituted alkoxycarbonylalkyl, optionally substituted cyanoalkyl, andoptionally substituted hydroxyalkyl; R² and R¹² may be independentlyselected at each occurrence from hydrogen, halogen, hydroxyl, haloalkyl,cyano, alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl; R³, R⁴,R⁵. R¹³, R¹⁴, and R¹⁵ may be independently selected at each occurrencefrom hydrogen, halogen, haloalkyl, cyano, alkyl, alkoxy, alkylthio,amide, amine, aryloxy, and aralkyloxy; R⁷, R⁸, and R¹¹ may beindependently selected at each occurrence from hydrogen, halogen,hydroxyl, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, andcarbocyclyl; and R⁶ may be selected from hydrogen, hydroxyl, and anoptionally substituted group selected from alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl,aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl,aralkylcarbonyl, acyloxy, alkyl sulfonyl, aryl sulfonyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, and amide.

For a compound of any of Formulas (III)-(VI), X may be —NR⁶—; Z may be—CR⁷R⁷; A may be —CR⁸R⁸—; W may be —CR¹¹R¹¹—, and n may be 0-2. Thecompound of Formula (IV) or (V) may be represented by the Formula (IVb):

and the compound of Formula (III) or (VI) may be represented by theFormula (IIIb):

In such embodiments, R¹ may be selected from halogen, alkyl, optionallysubstituted aralkyl, optionally substituted alkoxycarbonylalkyl,optionally substituted cyanoalkyl, and optionally substitutedhydroxyalkyl; R² and R¹² may be independently selected at eachoccurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl,alkoxy, alkylthio, amide, amine, and carbocyclyl; R³, R⁴, R⁵, R¹³, R¹⁴,and R¹⁵ may be independently selected at each occurrence from hydrogen,halogen, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine,aryloxy, and aralkyloxy; R⁷ and R⁸ may be independently selected at eachoccurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl,alkoxy, alkylthio, amide, amine, and carbocyclyl; and R⁶ may be selectedfrom an amine or amide protecting group, hydrogen, hydroxyl, and anoptionally substituted groups selected from alkyl, alkoxy, alkylthio,aryloxy, carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl,aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl,aralkylcarbonyl, acyloxy, alkyl sulfonyl, aryl sulfonyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, and amide.

In certain embodiments, for a compound of any of Formulas (III)-(VI), Xis —NR⁶— or —O—; Z is —C(O)—and —CR⁷R⁷—; A is independently selected ateach occurrence from —CR⁸R⁸— and —NR⁹—; W is absent or selected from—O—, —NR¹⁰—, and —CR¹¹R¹¹; and n is 0-3, with the proviso that when X is—NR⁶—, and Z is selected from —C(O)—and —CR⁷R⁷—, at least one A is —NR⁹—or W is —NR¹⁰—. In such embodiments, R¹ may be selected from halogen,alkyl, optionally substituted aralkyl, optionally substitutedalkoxycarbonylalkyl, optionally substituted cyanoalkyl, and optionallysubstituted hydroxyalkyl; R² and R¹² may be independently selected ateach occurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano,alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl; R³, R⁴, R⁵,R¹³, R¹⁴, and R¹⁵ may be independently selected at each occurrence fromhydrogen, halogen, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide,amine, aryloxy, and aralkyloxy; R⁷, R⁸, and R¹¹ may be independentlyselected at each occurrence from hydrogen, halogen, hydroxyl, haloalkyl,cyano, alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl; and R⁶,R⁹, and R¹⁰ may be selected from hydrogen, hydroxyl, and an optionallysubstituted group selected from alkyl, alkoxy, alkylthio, aryloxy,carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl, aralkyl,heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl,aralkylcarbonyl, acyloxy, alkyl sulfonyl, aryl sulfonyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, and amide.

For any of Formulas (III), (Ma), (IIIb), (IV), (IVa), (IVb), (V) and(VI), R⁶ may be selected from:

For any of Formulas (I), (II), (III), (Ma), (IIIb), (IV), (IVa) and(IVb), R¹ may be selected from:

While not being bound by a particular mechanism, any of the alkylationreactions discussed herein may proceed with or without a rearrangementof the allylic group. In the absence of an allylic rearrangement it isenvisioned that compounds subjected to the alkylation conditionsdescribed herein, where a compound of Formula (I) is converted to (II),a compound of Formula (III) is converted to (IV), a compound of Formula(Ma) is converted to (IVa) and a compound of Formula (IIIb) is convertedto (IVb), will otherwise display a substitution pattern in the productthat is the same as the substitution pattern in the substrate. Forexample, ring B, X, Z, A, W, n, and R⁶ to R¹¹ will not be altered fromthe substrate to the product under the reaction conditions and thecarbons bearing R¹² and R¹⁵ in the product will correspond with thecarbons bearing R² and R⁵ in the substrate, respectively.

In the event of an allylic rearrangement, it is envisioned thatcompounds subjected to the alkylation conditions described herein, wherea compound of Formula (I) is converted to (II), a compound of Formula(III) is converted to (IV), a compound of Formula (Ma) is converted to(IVa) and a compound of Formula (IIIb) is converted to (IVb), willotherwise display a substitution pattern in the product that is the sameas the substitution pattern in the substrate except that thesubstitution pattern in the product at the carbons bearing R¹², R¹⁴ andR¹⁵ is transposed relative to the starting material. That is, the carbonbearing R⁴ and R⁵ in the substrate becomes the carbon bearing the R¹²groups in the product, the carbon bearing the R² groups in the substratebecomes the carbon bearing R¹⁴ and R¹⁵ in the product, and the carbonbearing R³ in the substrate becomes the carbon bearing R¹¹ in theproduct. For example, ring B, X, Z, A, W, n, R¹ and R⁶ to R¹¹ will notbe altered from the substrate to the product under the reactionconditions but the carbons bearing R¹² to R¹⁵ in the product aretransposed relative to the carbons bearing R² to R⁵ in the substrate.

Under some circumstances, one or more substituents may be altered on theproduct relative to the substrate. For example, a protected hydroxylgroup in the starting material may become deprotected under thealkylation conditions of the method. Accordingly, in the variousembodiments disclosed herein, R¹², R¹³, R¹⁴, and R¹⁵ may be hydroxy inaddition to the other options disclosed above; for R¹³, R¹⁴, and R¹⁵,the resulting hydroxyalkene may tautomerize to the correspondingcarbonyl, such as to a ketone or aldehyde, as would be well understood.Under some circumstances, a protected amino group in the startingmaterial may become deprotected under the alkylation conditions of themethod. Accordingly, in the various embodiments disclosed herein, R¹²,R¹³, R¹⁴, and R¹⁵ may be amino in addition to the other optionsdisclosed above; for R¹³, R¹⁴, and R¹⁵, the resulting aminoalkene maytautomerize to the corresponding imine, such as to a ketimine oraldimine, as would be well understood.

A compound of any of Formulas (I), (II), (III), (Ma), (IIIb), (IV),(IVa), (IVb), (V) and (VI) may contain one or more asymmetric centers,chiral axes and chiral planes and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms and may be defined interms of absolute stereochemistry, such as (R)— or (S)— or, as (D)- or(L)- for amino acids. The present invention is intended to include allsuch possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)— and (S)—, or (D)- and(L)-isomers, e.g., ligands or substrates for the methods describedherein, may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as reverse phase HPLC. Theracemic mixtures may be prepared and thereafter separated intoindividual optical isomers or these optical isomers may be prepared bychiral synthesis. The enantiomers may be resolved by methods known tothose skilled in the art, for example by formation of diastereoisomericsalts which may then be separated by crystallization, gas-liquid orliquid chromatography, selective reaction of one enantiomer with anenantiomer specific reagent.

The compounds of the invention may be racemic or in certain embodiments,compounds of the invention may be enriched in one enantiomer. Forexample, a compound of any of Formulas (I), (II), (III), (Ma), (IIIb),(IV), (IVa), (IVb), (V) and (VI) such as a substrate or product of themethods described herein, may have 30% ee or greater, 40% ee or greater,50% ee or greater, 60% ee or greater, 70% ee or greater, 80% ee orgreater, 90% ee or greater, 95% ee or greater, or even 98% ee orgreater. In certain embodiments, compounds of the invention may havemore than one stereocenter. In certain such embodiments, compounds ofthe invention may be enriched in one or more diastereomer. For example,a compound of the invention may have 30% de or greater, 40% de orgreater, 50% de or greater, 60% de or greater, 70% de or greater, 80% deor greater, 90% de or greater, 95% de or greater, or even 98% de orgreater.

Transition Metal Catalysts

Preferred transition metal catalysts of the invention are complexes oftransition metals wherein the metal is selected from Groups 6, 8, 9 and10 in the periodic table. In preferred embodiments, the metal of thetransition metal catalyst is selected from molybdenum, tungsten,iridium, rhenium, ruthenium, nickel, platinum, and palladium. In morepreferred embodiments, the metal is palladium.

In one embodiment of the invention, a complex of a neutral transitionmetal is employed directly in the reaction. It should be appreciatedthat the air and moisture sensitivity of many complexes of neutraltransition metals will necessitate appropriate handling precautions.This may include the following precautions without limitation:minimizing exposure of the reactants to air and water prior to reaction;maintaining an inert atmosphere within the reaction vessel; properlypurifying all reagents; and removing water from reaction vessels priorto use. Exemplary neutral transition metal catalysts include, withoutlimitation, Mo(CO)₆, Mo(MeCN)₃(CO)₃, W(CO)₆, W(MeCN)₃(CO)₃,[Ir(1,5-cyclooctadiene)Cl]₂, [Ir(1,5-cyclooctadiene)Cl]₂,[Ir(1,5-cyclooctadiene)Cl]₂, Rh(PPh₃)₃Cl, [Rh(1,5-cyclooctadiene)Cl]₂,Ru(pentamethylcyclopentadienyl)(MeCN)₃PF₆, Ni(1,5-cyclooctadiene)₂,Ni[P(OEt)₃]₄, tris(dibenzylideneacetone)dipalladium(0),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct,bis(4-methoxybenzylidene)acetone)dipalladium(0), Pd(OC(═O)CH₃)₂,Pd(3,5-dimethyoxy-dibenzylideneacetone)₂, PdCl₂(R²³CN)₂;PdCl₂(PR²⁴R²⁵R²⁶)₂; [Pd(η³-allyl)Cl]₂; and Pd(PR²⁴R²⁵R²⁶)₄, wherein R²³,R²⁴, R²⁵, and R²⁶ are independently selected from H, hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, andsubstituted heteroatom-containing hydrocarbyl. In particularembodiments, the transition metal catalysttris(dibenzylideneacetone)dipalladium, Pd₂(dba)₃, orbis(4-methoxybenzylidene)acetone) dipalladium, Pd₂(pmdba)₃, ispreferred.

To improve the effectiveness of the catalysts discussed herein,additional reagents may be employed as needed, including, withoutlimitation, salts, solvents, and other small molecules. Preferredadditives include AgBF₄, AgOSO₂CF₃, AgOC(═O)CH₃, PPh₃, P(n-Bu)₃, andbipyridine. These additives are preferably used in an amount that is inthe range of about 1 equivalent to about 5 equivalents relative to theamount of the catalyst.

The neutral oxidation state of the transition metal can also be obtainedin situ, by the reduction of transition metal complexes that areinitially in a higher oxidation level. An exemplary method for reductionof the transition metal complex is with the use of nucleophilic reagentsincluding, without limitation, NBu4OH, tetrabutylammoniumdifluorotriphenylsilicate (TBAT), tetrabutylammonium fluoride (TBAF),4-dimethylaminopyridine (DMAP), NMe₄OH(H₂O)₅,KOH/1,4,7,10,13,16-Hexaoxacyclooctadecane, EtONa,TBAT/Trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane, and mixturesthereof. When a nucleophilic reagent is needed for the reduction of themetal complex, the nucleophilic reagent is used in an amount in therange of about 1 mol % to about 20 mol % relative to the reactant, morepreferably in the range of about 1 mol % to about 10 mol % relative tothe substrate, and most preferably in the range of about 5 mol % toabout 8 mol % relative to the substrate.

Exemplary transition metal complexes with a +2 oxidation state include,without limitation,allylchloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium(II),([2 S,3 S]-bis[diphenylphosphino]butane)(η³-allyl)palladium(II)perchlorate,[S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η³-allyl)palladium(II)hexafluorophosphate (i.e., [Pd(S-tBu-PHOX)(allyl)]PF₆), andcyclopentadienyl(η³-allyl) palladium(II), with[Pd(s-tBu-PHOX)(allyl)]PF₆ and cyclopentadienyl(η³-allyl)palladium(II)being most preferred. The amount of catalyst to be used in the reactionsof the invention is generally measured in relation to the amount ofsubstrate that is present. For the reactions of the invention, the metalfrom the catalyst is present in an amount ranging from about 1 mol % toabout 20 mol % relative to the substrate. More preferably, the metalfrom the catalyst is present in an amount ranging from about 1 mol % toabout 10 mol %, such as about 2 mol % to about 7 mol %, such as about 5mol % relative to the substrate. By “metal from the catalyst” is meantthe equivalents (relative to the substrate) of transition metal atoms.Thus, for example, 5 mol % of tris(dibenzylideneacetone)dipalladium(0)provides 10 mol % of metal atoms relative to the substrate. In certainembodiments, the amount of catalyst in relation to the substrate isselected from 2-8 mol %, such as about 5 mol %.

Ligands

One aspect of the invention is the enantioselectivity of the methods.Enantioselectivity is a result of the presence of chiral ligands duringthe reactions. Without being bound by theory, enantioselectivity resultsfrom the asymmetric environment that is created around the metal centerby the presence of chiral ligands. The chiral ligand forms a complexwith the transition metal, thereby occupying one or more of thecoordination sites on the metal and creating an asymmetric environmentaround the metal center. This complexation may or may not involve thedisplacement of achiral ligands already complexed to the metal. Whendisplacement of one or more achiral ligands occurs, the displacement mayproceed in a concerted fashion, i.e., with both the achiral liganddecomplexing from the metal and the chiral ligand complexing to themetal in a single step. Alternatively, the displacement may proceed in astepwise fashion, i.e., with decomplexing of the achiral ligand andcomplexing of the chiral ligand occurring in distinct steps.Complexation of the chiral ligand to the transition metal may be allowedto occur in situ, i.e., by admixing the ligand and metal before addingthe substrate. Alternatively, the ligand-metal complex can be formedseparately, and the complex isolated before use in the alkylationreactions of the present invention. Once coordinated to the transitionmetal center, the chiral ligand influences the orientation of othermolecules as they interact with the transition metal catalyst.Coordination of the metal center with a it-allyl group, and reaction ofthe substrate with the 7C -allyl-metal complex are dictated by thepresence of the chiral ligand. The orientation of the reacting speciesdetermines the stereochemistry of the products.

Many factors determine the ability of the chiral ligand to influence theorientation of the reacting species, and thereby determine thestereochemistry of the products. For example, shape and size (i.e.,sterics), denticity (mono- or bidentate), and electronic propertiesaffect the ligand-metal complex as well as the interaction of themetal-ligand complex with the nucleophile. These factors can varysubstantially between ligands, resulting in correspondingly largedifferences in the success of the ligands as promoters ofenantioselective alkylation. For any given substrate, some ligands mightprovide relatively high product yield, while other ligands affectrelatively high enantiopurity of the product. Still other ligands mayprovide both high yield and high enantiopurity, while still otherligands might provide neither. It should be understood that properligand selection for any given substrate will influence the products ofthe reaction.

Generally, the chiral ligand is present in an amount in the range ofabout 0.75 equivalents to about 10 equivalents relative to the amount ofmetal from the catalyst, preferably in the range of about 0.75 to about5 equivalents relative to the amount of metal from the catalyst, andmost preferably in the range of about 0.75 to about 1.25, such as about1.25 equivalents relative to the amount of metal from the catalyst.Alternatively, the amount of the chiral ligand can be measured relativeto the amount of the substrate. Then, the chiral ligand is present in anamount ranging from about 1 mol % to about 20 mol %, more preferablyfrom about 2.5 mol % to about 13 mol % such as about 12.5 mol % relativeto the substrate.

Chiral ligands of the invention may be bidentate or monodentate orligands with higher denticity (i.e., tridentate, tetradentate, etc.) canbe used. Preferably, the ligand will be substantially enantiopure. By“enantiopure” is meant that only a single enantiomer is present. In manycases, substantially enantiopure ligands can be purchased fromcommercial sources.

Exemplary chiral ligands may be found in U.S. Pat. No. 7,235,698, theentirely of which is incorporated herein by reference. Preferred chiralligands of the invention include the PHOX-type chiral ligands such as(R)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline,(R)-2-[2-(diphenylphosphino)phenyl]-4-phenyl-2-oxazoline,(S)-2-[2-(diphenylphosphino)phenyl]-4-benzyl-2-oxazoline,(S)-2-[2-(diphenylphosphino)phenyl]-4-tert-butyl-2-oxazoline((S)-t-BuPHOX) and(S)-2-(2-(bis(4-(Trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phenyl)-4-(tent-butyl)-4,5-dihydrooxazole((S)-(CF₃)₃-t-BuPHOX). In preferred embodiments, the PHOX type chiralligand is selected from (S)-t-BuPHOX and (S)-(CF₃)₃-t-BuPHOX).

Where a chiral ligand is used, the reactions of the invention may enrichthe stereocenter bearing R¹ in the product relative to the enrichment atthis center, if any, of the starting material. For example, a product ofthe methods described herein may have 30% ee or greater, 40% ee orgreater, 50% ee or greater, 60% ee or greater, 70% ee or greater, 80% eeor greater, 90% ee or greater, 95% ee or greater, or even 98% ee orgreater, even where this % ee is greater than the % ee of the startingmaterial, such as 0% ee (racemic). In embodiments where the startingmaterial has more than one stereocenter, reactions of the invention mayenrich the stereocenter bearing R¹ relative to the enrichment at thiscenter, if any, of the starting material, and substantiallyindependently of the stereochemical disposition/enrichment of any otherstereocenters of the molecule. For example, a product of the methodsdescribed herein may have 30% de or greater, 40% de or greater, 50% deor greater, 60% de or greater, 70% de or greater, 80% de or greater, 90%de or greater, 95% de or greater, or even 98% de or greater at thestereocenter of the product bearing R¹.

Alkylation Conditions

The reactions of the invention are preferably carried out in solventunder an inert atmosphere. Appropriate solvents include, withoutlimitation, hydrocarbons, substituted hydrocarbons,heteroatom-containing hydrocarbons, and substitutedheteroatom-containing hydrocarbons. Preferred solvents include ethers,amines, ketones, aromatic hydrocarbons, heteroatom-containing aromatichydrocarbons, and substituted aromatic hydrocarbons. In certainembodiments, the solvent is selected from one or more polar aprotic andnonpolar solvents. Examples of preferred solvents include 1,4-dioxane,tetrahydrofuran, methyl-tert-butyl ether, diethyl ether, toluene,hexanes, benzene, diisopropyl ether, ethyl acetate, triethylamine,anisole, acetone, fluorobenzene, and diglyme or mixtures thereof.Supercritical fluids can also be used as solvents, with carbon dioxiderepresenting one such solvent. Reaction temperatures range from 0° C. to100° C., with 20° C. to 60° C. being preferred, and 20° C. to 25° C.(i.e., room temperature) being particularly preferred. In particularembodiments, the reaction temperature is is below about 60° C., belowabout 50° C., below about 40° C., or below about 30° C. The reactiontime will generally be in the range of 1 hour to 24 hours. In certainembodiments, instruments such as a microwave reactor may be used toaccelerate the reaction time. Pressures range from atmospheric topressures typically used in conjunction with supercritical fluids, withthe preferred pressure being atmospheric.

IV. Additional Compounds and Methods of the Invention

According to embodiments of the present invention compounds useful aseither substrates for the creation of building blocks leading to targetcompounds or as building blocks include compounds represented by thefollowing Chemical Formula A. As discussed here, these compounds can beused as substrate compounds useful in the method noted above anddescribed in detail below. Also, these compounds may be used asreactants in other methods and reaction schemes to make other compounds,e.g., some naturally occurring compounds that may be biologicallyactive. Chemical Formula A

In Chemical Formula A, z is either 0 or 1, and Q is a heteroatom, forexample, N, O, P, S or a halogen such as Cl, I, Br or F. In someembodiments, for example, Q is N or O. Each of R1 through R10 isindependently selected from hydrogen, substituted or unsubstitutedhydrocarbyl groups, substituted or unsubstituted heteroatom containinghydrocarbyl groups, or functional groups. However, in some embodiments,R3 is not hydrogen. In some embodiments, in which z is 0 and R8 and R9combine to form a carbonyl group (as discussed further below), R3 isalso not phenyl or substituted phenyl. In yet other embodiments, inwhich z is 0 and R8 and R9 combine to form a carbonyl group (asdiscussed further below), R3 is not a simple carbonyl group. However, insome embodiments, R3 may be a substituted carbonyl group, e.g., acarbonyl group substituted hydrocarbyl group or heteroatom containinghydrocarbyl group or functional group. In some embodiments, though, R3does not include any carbonyl groups, whether substituted orunsubstituted. In yet other embodiments, in which z is 0 and R8 and R9combine to form a carbonyl group (as discussed further below), R3 is notan ethyl group. However, in some embodiments, R3 may be a substitutedethyl group, and R3 may be any other alkyl group (or other group asdescribed above). In some embodiments, though, R3 is not an ethyl groupor a substituted ethyl group. Also, in some embodiments, the carbon atomto which the R3 group is attached is a chiral, stereogenic center, i.e.,R3 and Y are not the same.

Y may be selected from hydrogen, heteroatoms, substituted orunsubstituted hydrocarbyl groups, substituted or unsubstitutedheteroatom containing hydrocarbyl groups, or functional groups.Additionally, any two or more adjacent R and Y groups can optionallycombine to form a carbonyl group on the underlying atom. For example, insome embodiments, R8 and R9 combine to form a carbonyl group, as shownin the below Formula A(i).

Also, any two or more adjacent R and Y groups can optionally combine toform a ring, e.g., a cyclic, heterocyclic, aryl or heteroaryl ring.Indeed, in some embodiments, although Formula 1 depicts an acyclicheteroatom containing compound, Formula 1 also encompasses cyclic,heterocyclic, aryl and heteroaryl compounds. Also, in some embodiments,while R6 and R10 may combine to form nearly any ring structure, R6 andR10 do not form a substituted or unsubstituted benzene ring. Similarly,in some embodiments, while R4 and R6 may combine to form nearly any ringstructure, R4 and R6 do not form a substituted or unsubstituted benzenering. In other embodiments, R6 and R10 do not form any aromatic ring,and R4 and R6 do not form any aromatic ring.

In embodiments in which R2 and Y combine to form a ring, in someembodiments, the atom in the ring directly adjacent the Q atom (i.e.,the atom on the opposite side of the Q atom to the carbon atom carryingthe R8 and R9 groups) is not a chiral center. More specifically, anysubstituents on that atom are the same as each other, and that atom doesnot include two different substituents.

For example, in some embodiments, the R2 group on the Q atom, and the Ygroup combine to form a ring with the Q atom, the carbon atom to whichthe Y group is attached, and the intervening carbon atom. The ringformed between the R2 group and the Y group can be any type of ring withany number of ring atoms. However, the ring formed from the combinationof R2 and Y does not form a benzene ring or ortho-disubstituted benzenering. In some embodiments, though, R2 and Y may form other substitutedbenzene rings. In other embodiments, however, R2 and Y do not form anykind of benzene ring.

In some exemplary embodiments, for example, the ring formed between theR2 group and the Y group may include one or more additional heteroatoms(i.e., additional to the Q atom depicted in Formula 1). In theseembodiments, the compounds of Formula 1 may be represented by Formula B,below.

In Formula B, z is 0 or 1, and R1 through R10 are the same as definedabove with respect to Formula A. Each of Q1 and Q2 are as defined abovewith respect to Q1, and are each independently selected fromheteroatoms, e.g., N, O, S, P or halogens, such as Cl, I, F or Br. Insome embodiments, for example, each of Q1 and Q2 is independentlyselected from N or O. Additionally, similar to that described above withrespect to Formulae 1 and 1(a), any two or more adjacent R groups canoptionally combine to form a carbonyl group on the underlying atom. Forexample, in some embodiments, R8 and R9 combine to form a carbonylgroup, as shown in the below Formula 2(a).

Also, in Formula B, each of x, n and m can be any integer of 0 orgreater. When x is greater than 1, the plurality of Q2 heteroatoms maybe the same as or different from each other. In some embodiments, forexample, each of x, n and m is independently 0, 1, 2, 3 or 4. In someexemplary embodiments, when x and n are both 0, m may be 1, 2, 3 or 4.Conversely, when x and m are both 0, n may be 1, 2, 3 or 4. Theseconfigurations yield compounds having the Formulae B(ii) or B(iii)(where R8 and R9 combine to form a carbonyl group) below. Also, while mand n are defined here such that the ring depicted in Formula B has upto 7 ring atoms, it is understood that the size of the ring in Formula Bis not particularly limited, and n and m can be any integerscorresponding to any ring size. For example, in some embodiments, n andm are integers such that the resulting ring depicted in Formula B hasfrom 3 to 12 ring atoms. In some embodiments for example, n and m areintegers such that the resulting ring has from 3 to 10 ring atoms. Inother embodiments, n and m are integers such that the resulting ring hasfrom 5 to 7 ring atoms.

Alternatively, in some embodiments, when x is 1, n and m may be anyinteger from 0 to 4 such that the sum of n and m may be 0, 1, 2 or 3.For example, in some embodiments, when x is 1, n may be 0 and m may be0, 1, 2 or 3. In other embodiments, when x is 1, n may be 1 and m may be0, 1 or 2. In still other embodiments, when x is 1, n may be 2 and m maybe 0 or 1. In yet other embodiments, when x is 1, n may be 3 and m maybe 0. Conversely, in some embodiments, when x is 1, m may be 0 and n maybe 0, 1, 2 or 3. In other embodiments, when x is 1, m may be 1 and n maybe 0, 1 or 2. In still other embodiments, when x is 1, m may be 2 and nmay be 0 or 1. In yet other embodiments, when x is 1, m may be 3 and nmay be 0. These configurations yield compounds of Formula B in whichthere are two heteroatoms, and include all configurations of the twoheteroatoms on the ring. Specifically, these configurations cover everypossible position of the second heteroatom (Q2) on the ring depicted inFormula B. Also, while m and n are defined here such that the ringdepicted in Formula B has up to 7 ring atoms, it is understood that thesize of the ring in Formula B is not particularly limited, and n and mcan be any integers corresponding to any ring size, as discussed above.For example, in some embodiments, n and m are integers such that theresulting ring depicted in Formula B has from 3 to 12 ring atoms, forexample 3 to 10 ring atoms or 5 to 7 ring atoms.

In some embodiments, the ring may include the Q atom depicted inFormulae A and B as the only heteroatom, and include any number ofadditional carbon atoms in the ring. Alternatively, however, the ringdepicted in Formulae B and B(i) through B(iii) can have any number ofheteroatoms positioned anywhere on the ring. For example, as shown inFormula B and B(i) above, the ring may include the heteroatom depictedin Formulae A and B separated from a group of one or more additionalheteroatoms by one or more carbon atoms, or the ring may include two ormore heteroatoms that are adjacent each other within the ring. However,according to other embodiments, the ring depicted in Formula B mayinclude three or more heteroatoms which may be adjacent one another orseparated from each other by at least one carbon atom. Thisconfiguration is depicted in Formulae B(iv) and B(v) (where R8 and R9combine to form a carbonyl group) below.

In Formula B(iv) and B(v), z is 0 or 1, each of Q1, Q2 and Q3 is asdefined above with respect to Q1, and are each independently aheteroatom, for example, O, N, S, P, or a halogen such as Cl, I, Br orF. Each of R1 through R10 is also as described above with respect toFormulae A, B and B(i) through 2(iii). Each of a, b and c isindependently an integer of 0 or greater. In some exemplary embodiments,each of a, b and c may be independently an integer of 0, 1 or 2. Forexample, in some embodiments, each of a, b and c is 0, yielding a fivemembered ring including three adjacent heteroatoms. In otherembodiments, a is 1 and b and c are both 0, yielding a six membered ringin which Q2 and Q3 are adjacent one another and Q2 is separated from Q1by a carbon atom. In still other embodiments, a is 2 and b and c areboth 0, yielding a seven membered ring in which Q2 and Q3 are adjacentone another and Q2 is separated from Q1 by two carbon atoms.

According to other embodiments, b is 1 and a and c are both 0, yieldinga six membered ring in which Q1 and Q2 are adjacent one another and Q2is separated from Q3 by a carbon atom. In still other embodiments, b is2 and a and c are both 0, yielding a seven membered ring in which Q1 andQ2 are adjacent one another and Q2 is separated from Q3 by two carbonatoms.

In other embodiments, c is 1 and a and b are both 0, yielding a sixmembered ring in which Q1, Q2 and Q3 are adjacent one another. In stillother embodiments, c is 2 and a and b are both 0, yielding a sevenmembered ring in which Q1, Q2 and Q3 are adjacent one another. Also,while a, b and c are defined here such that the ring depicted inFormulae B, B(iv) and B(v) has up to 7 ring atoms, it is understood thatthe size of the ring in Formulae B, B(iv) and B(v) is not particularlylimited, and a, b and c can be any integers corresponding to any ringsize, as discussed above. For example, in some embodiments, a, b and care integers such that the resulting ring depicted in Formulae B, B(iv)and B(v) has from 3 to 12 ring atoms, for example 3 to 10 ring atoms or5 to 7 ring atoms.

In some exemplary embodiments, the ring depicted in Formula B mayinclude four heteroatoms, and the four heteroatoms may be placed on thering in any manner. For example, some of the heteroatoms may be spacedfrom each other by one or more ring carbon atoms while others areadjacent, or all heteroatoms may be adjacent each other, or allheteroatoms may be spaced from each other by one or more ring carbonatoms.

Additionally, although the rings discussed above are depicted anddescribed as fully saturated, according to some embodiments of thepresent invention, any of the rings may be unsaturated (i.e., mono- orpoly-unsaturated). To account for these compounds, the heteroatomcontaining substrate of Formula A may be represented by Formulae C orC(i) (where R8 and R9 combine to form a carbonyl group) below.

In Formulae C and C(i), z is 0 or 1, and Q1 and R1 through R10 are asdefined above with respect to Formulae A, B and B(i) through B(v). Eachof A, B and D is independently a carbon atom or a heteroatom. However,in some embodiments, in which d is 1 or greater, the A atom locateddirectly adjacent the Q1 atom is not a chiral center. More specifically,the Ra and Rb sub stituents on that atom are the same as each other, andare not two different substituents. Also, the ring formed from Q1, A, Band D is not a benzene ring or an ortho-disubstituted benzene ring. Insome embodiments, though, the ring may be any other substituted benzenering. In other embodiments, however, the ring is not any kind of benzenering.

Each of Ra, Rb, R, Rd, Re and Rf may be independently selected fromhydrogen atoms, substituted or unsubstituted hydrocarbyl groups,substituted or unsubstituted heteroatom containing hydrocarbyl groups,halogens or functional groups. However, as discussed above, in someembodiments, in which d is 1 or greater, the A atom located directlyadjacent the Q1 atom is not a chiral center, and the Ra and Rbsubstituents on that atom are the same as each other. In someembodiments, however, one R group on each of two adjacent ring atoms cancombine to form a bond, thereby creating a double bond within the ringstructure. Specifically, each of Ra through Rf is either: independentlyhydrogen, a substituted or unsubstituted hydrocarbyl group, asubstituted or unsubstituted heteroatom containing hydrocarbyl group, ora functional group; or combines with another of Ra through Rf to form adouble bond. For example, R1 and one of the Ra groups may combine toform a double bond, or one of the Rb groups and one of the Rc groups maycombine to form a double bond within the ring, or one of the Rd groupsand one of the Re groups may combine to form a double bond within thering. Any number of double bonds may be formed within the ringstructure, and the ring structure may be heteroaryl in nature.Alternatively or additionally, two adjacent R groups on the same ringatom (e.g., Ra and Rb, or Rc and Rd, or Re and Rf) can combine to form acarbonyl group on the ring atom.

Each of d, e and f is independently an integer of 0 or greater, forexample, an integer of 0, 1, 2, 3, or 4. When d, e or f is greater than1, the plurality of A, B or D atoms, and the plurality of Ra, Rb, Rc,Rd, Re or Rf groups may be the same as or different from each other.Also, although Formulae C and C(i) above depict a six membered ring, itis understood from the definitions of d, e and f that the ring is notlimited to six members, and can have any number of ring atoms, asdiscussed above with respect to Formulae A, B and B(i) through B(v).Indeed, in some embodiments, the ring has from 3 to 12 ring atoms, forexample 3 to 10 ring atoms or 5 to 7 ring atoms.

Also, in the rings discussed above, any of the ring atoms, whethercarbon or heteroatom, can be substituted with a substituted orunsubstituted hydrocarbyl group, substituted or unsubstituted heteroatomcontaining hydrocarbyl group, a halogen or a functional group. Indeed,although the rings depicted in Formulae B and B(i) through B(v) aboveare depicted with hydrogen atoms on each of the ring atoms, any or allof the hydrogen atoms on any or all of the ring atoms may be substitutedwith the substituents described above. As shown in Formula C, forexample, each of the ring atoms (Q1, A, B and/or D) may include R groupsthat can be hydrogen, a substituted or unsubstituted hydrocarbyl group,a substituted or unsubstituted heteroatom containing hydrocarbyl group,a halogen or a functional group.

In some embodiments of the present invention, building block compoundscreated from substrate compounds of Formula A are represented by thebelow Formula D. The compounds of Formula D include compounds created bythe palladium catalyzed decarboxylative alkylation of substratecompounds represented by Formula A in which z is 1, Q (or Q1) is O andR8 and R9 combine to form a carbonyl group.

As noted above, compounds of Formula D can be made through the palladiumcatalyzed decarboxylative alkylation of a lactone satisfying one ofFormulae A, B or C above. Specifically, the compound of Formula D willresult when a compound of Formula C (in which z is 1, Q1 is O and R8 andR9 combine to form a carbonyl group) is subjected to palladium catalyzeddecarboxylative alkylation. In Formula D, A, B, D, Ra, Rb, Rc, Rd, Re,Rf, R3, R4, R5, R6, R7 and R10 are as described above with respect to Athrough C. Each of Ra, Rb, R, Rd, Re and Rf may be independentlyselected from hydrogen atoms, substituted or unsubstituted hydrocarbylgroups, substituted or unsubstituted heteroatom containing hydrocarbylgroups, halogens or functional groups. However, similar to thatdiscussed above with respect to Formulae A through C, in someembodiments, in which d is 1 or greater, the A atom that is directlyadjacent the OH group is not a chiral center. More specifically, the Raand Rb groups on the A atom that is directly adjacent the OH group arethe same as each other. In some embodiments, however, one R group oneach of two adjacent ring atoms can combine to form a bond, therebycreating a double bond within the ring structure. Specifically, each ofRa through Rf is either: independently hydrogen, a substituted orunsubstituted hydrocarbyl group, a substituted or unsubstitutedheteroatom containing hydrocarbyl group, or a functional group; orcombines with another of Ra through Rf to form a double bond.

In Formulae A, A(i), B, B(i) through B(v), C, C(i), and D above, theheteroatom containing compounds are depicted and described as includinga terminal alkenyl group. This position of the alkenyl group may beimportant in the palladium catalyzed decarboxylative alkylationreaction. However, for other uses of the heteroatom containing compoundsdescribed here (e.g., as reactants in other reactions), the alkenylgroup need not be positioned at the terminal end of the compound.

Instead, the alkenyl group can be positioned elsewhere in the compound.Also, the position of the alkenyl group can be modified after thecompletion of the palladium catalyzed decarboxylative alkylationreaction. For example, in compounds of Formula A through C in which z is0, the alkenyl group can be positioned as shown in the below FormulaeA(ii) and A(iii) (where R8 and R9 combine to form a carbonyl group) inwhich z is 0.

In Formula A(ii) and A(iii), Q, Y and R1 through R10 are as describedabove with respect to Formulae 1, 2, 2(a), 2(b) and 3.However, inFormulae A(ii) and A(iii), z is 0. Also, R11 is selected from the samesubstituents described above for R1 through R10. Specifically, each ofR1 through R11 may be independently selected from hydrogen, substitutedor unsubstituted hydrocarbyl groups, substituted or unsubstitutedheteroatom containing hydrocarbyl groups, halogens or functional groups.

In other embodiments, in which the compound is analogous to the compoundrepresented by Formula D, the alkenyl group can be positioned as shownin the below Formula D(i).

In Formula D(i), A, B, D, Ra through Rf, d, e, f, and R3 through R10 areas described above. Also, R11 is selected from the same substituentsdescribed above for R1 through R10. Specifically, each of R1 through R11may be independently selected from hydrogen, substituted orunsubstituted hydrocarbyl groups, substituted or unsubstitutedheteroatom containing hydrocarbyl groups, halogens or functional groups.Each of Ra, Rb, Rc, Rd, Re and Rf may be independently selected fromhydrogen atoms, substituted or unsubstituted hydrocarbyl groups,substituted or unsubstituted heteroatom containing hydrocarbyl groups,halogens or functional groups. However, similar to that discussed abovewith respect to Formulae A through C, in some embodiments, in which d is1 or greater, the A atom that is directly adjacent the OH group is not achiral center. More specifically, the Ra and Rb groups on the A atomthat is directly adjacent the OH group are the same as each other. Insome embodiments, however, one R group on each of two adjacent ringatoms can combine to form a bond, thereby creating a double bond withinthe ring structure. Specifically, each of Ra through Rf is either:independently hydrogen, a substituted or unsubstituted hydrocarbylgroup, a substituted or unsubstituted heteroatom containing hydrocarbylgroup, or a functional group; or combines with another of Ra through Rfto form a double bond. In Formulae A, A(i), B, B(i) through B(v), C,C(i), and D above, the terminal alkenyl group can be reacted (e.g.,hydrogenated) to make a corresponding alkyl derivative having the belowFormula A(iv) and A(v) (in which the R8 and R9 groups combine to form acarbonyl group, and in which z is 0.

In Formula A(iv) and A(v), Q, Y and R1 through R11 are as describedabove with respect to Formulae A through C. Also, R′ and R″ areindependently selected from the same substituents described above for R1through R11. Specifically, each of R1 through R11 and R′ and R″ may beindependently selected from hydrogen, substituted or unsubstitutedhydrocarbyl groups, substituted or unsubstituted heteroatom containinghydrocarbyl groups, halogens or functional groups. Also, it isunderstood that although Formula A through C are discussed and depictedabove as including the terminal alkenyl group, any of those formulae mayinstead include the terminal alkyl discussed here and depicted inFormulae A(iv) and A(v).

In some embodiments of the present invention in which the heteroatom isa nitrogen atom, the R group on the heteroatom (i.e., Q, Q1, Q2, Q3, orother heteroatoms in the substrates of Formulae A through C) can be anamine protecting group. Those of ordinary skill in the art would readilyunderstand what is meant by “amine protecting group.” However, somenonlimiting examples of suitable amine protecting groups includecarboxybenzyl (Cbz) groups, p-methoxybenzyl carbonyl (Moz or MeOZ)groups, tent-butyloxycarbonyl (BOC) groups, fluorenylmethyloxycarbonyl(FMOC) groups, acetyl (Ac) groups, benzoyl (Bz) groups, benzyl (Bn)groups, carbamate groups, p-methoxybenzyl (PMB) groups, dimethoxybenzyl(DMPM) groups, p-methoxyphenyl (PMP) groups, tosyl (Ts) groups,sulfonamide (Nosyl & Nps) groups, methoxybenzoyl groups (OMe-Bz), andfluorobenzoyl groups (F-Bz). For example, in some embodiments, the amineprotecting group is selected from tosyl groups (Ts), butyloxycarbonylgroups (BOC), carbobenzyloxy groups (Cbz), fluoreneylmethyloxycarbonylgroups (FMOC), acetyl groups (Ac), methoxybenzoyl groups (OMe-Bz),fluorobenzoyl groups (F-Bz), and benzoyl groups (Bz).

In some alternate embodiments, however, the R group(s) on the N can behydrogen, a substituted or unsubstituted hydrocarbyl group, asubstituted or unsubstituted heteroatom containing hydrocarbyl group, ora functional group. For example, in some embodiments, the R group(s) onthe N atom may be H or OH. In some exemplary embodiments, for example, zis 0 and R1 is H or OH.

As used herein, the term “hydrocarbyl groups” refers to univalenthydrocarbon radicals containing from 1 to 30 carbon atoms, for example,from 1 to 24 carbon atoms or 1 to 12 carbon atoms. The term “hydrocarbylgroups” includes linear, branched, cyclic, saturated and unsaturatedspecies, for example, alkyl groups, alkenyl groups, alkynyl groups, arylgroups, and the like. Also, as used herein, the term “substituted,” asin “substituted hydrocarbyl groups,” refers to a hydrocarbyl group inwhich one or more hydrogen atoms (bonded to a carbon atom) is replacedwith one or more non-hydrogen functional groups.

The term “functional groups” would be readily understood to those ofordinary skill in the art. However, some nonlimiting examples ofsuitable functional groups for use in the Formulae and substratesdescribed above include halogens, hydroxyl groups, sulfhydryl groups,alkoxy groups (e.g., having from 1 to 24 carbon atoms), alkenyloxygroups (e.g., having from 2 to 24 carbon atoms), alkynyloxy groups(e.g., having from 2 to 24 carbon atoms), aryloxy groups (e.g., havingfrom 5 to 24 carbon atoms), acyl groups including alkylcarbonyl groupsof the formula —CO-alkyl (e.g., having from 2 to 24 carbon atoms) andarylcarbonyl groups of the formula —CO-aryl (e.g., having from 6 to 24carbon atoms), acyloxy groups having the formula —O-acyl, alkoxycarbonylgroups having the formula —(CO)—O-alkyl (e.g., having from 2 to 24carbon atoms), carbonyl groups (including aldehyde moieties having theformula —(CO)—H) and ketone moieties having the formula —(CO)—R where Ris any hydrocarbyl group), aryloxycarbonyl groups having the formula—(CO)—O-aryl (e.g., having from 6 to 24 carbon atoms), halocarbonylgroups having the formula —CO—X (where X is a halogen), alkylcarbonatogroups having the formula —O—(CO)—O-alkyl (e.g., having from 2 to 24carbon atoms), arylcarbonato groups having the formula —O—(CO)—O-aryl(e.g., having from 6 to 24 carbon atoms), carboxyl groups having theformula —COOH, carboxylato groups having the formula —COO⁻, carbamoylgroups having the formula —(CO)—NH, mono-alkyl substituted carbamoylgroups having the formula —(CO)—NH-alkyl (e.g., the alkyl group havingfrom 1 to 24 carbon atoms), di-alkyl substituted carbamoyl groups havingthe formula —(CO)—N-alkyl₂ (e.g., each alkyl group having from 1 to 24carbon atoms), mono-aryl substituted carbamoyl groups having the formula—(CO)—NH-aryl (e.g., the aryl group having from 6 to 24 carbon atoms),di-aryl substituted carbamoyl groups having the formula —(CO)—N-aryl₂(e.g., each aryl group having from 6 to 24 carbon atoms),di-N(alkyl)-N(aryl) substituted carbamoyl groups having the formula—(CO)—N-(alkyl)(aryl), thiocarbamoyl groups having the formula—(CS)—NH₂, carbamido groups having the formula —NH—(CO)—NH₂, cyanogroups, isocyano groups, cyanato groups, isocyanato groups,isothiocyanato groups, azido groups, formyl groups, thioformyl groups,amino groups, mono-alkyl substituted amino groups (e.g., the alkyl grouphaving from 1 to 24 carbon atoms), di-alkyl substituted amino groups(e.g., the alkyl group having from 1 to 24 carbon atoms), mono-arylsubstituted amino groups (e.g., the aryl group having from 6 to 24carbon atoms), di-aryl substituted amino groups (e.g., each aryl grouphaving from 6 to 24 carbon atoms), alkylamido groups having the formula—NH—(CO)-alkyl (e.g., having from 2 to 24 carbon atoms), arylamidogroups having the formula —NH—(CO)-aryl (e.g., having from 6 to 24carbon atoms), imino groups having the formula —CR═NH (where R ishydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), alkyl imino groupshaving the formula —CR═N-alkyl (where R is hydrogen, alkyl, aryl,aralkyl, alkaryl, etc.), aryl imino groups having the formula —CR═N-aryl(where R is hydrogen, alkyl, aryl, aralkyl, alkaryl, etc.), nitrogroups, nitroso groups having the formula —NO, sulfo groups having theformula —SO₂—OH, sulfonato groups having the formula —SO₂—O⁻,alkylsulfanyl groups having the formula —S-alkyl (also called,interchangeably, alkylthio groups), arylsulfanyl groups having theformula —S-aryl (also called, interchangeably arylthio groups),alkylsulfinyl groups having the formula —(SO)-alkyl, arylsulfinyl groupshaving the formula —(SO)-aryl, alkylsulfonyl groups having the formula—SO₂-alkyl, arylsulfonyl groups having the formula —SO₂-aryl, borylgroups having the formula —BH₂, borono groups having the formula—B(OH)₂, boronato groups having the formula —B(OR)₂ (where R is alkyl oranother hydrocarbyl group), phosphono groups having the formula—P(O)(OH)₂, phosphonato groups having the formula —P(O)(O⁻)₂,phosphinato groups having the formula —P(O)(O⁻), phospho groups havingthe formula —PO₂, and phosphino groups having the formula —PH₂.

In addition to, or instead of, being substituted with a functionalgroup, the substituted species may be substituted with hydrocarbylgroups, for example, alkyl groups (e.g., having from 1 to 24 carbonatoms, or from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms),alkenyl groups (e.g., having from 2 to 24 carbon atoms, or from 2 to 13carbon atoms, or from 2 to 6 carbon atoms), alkynyl groups (e.g., havingfrom 2 to 24 carbon atoms, or from 2 to 12 carbon atoms, or from 2 to 6carbon atoms), aryl groups (e.g., having from 5 to 24 carbon atoms, orfrom 5 to 14 carbon atoms), alkaryl groups (i.e., aryl with an alkylsubstituent, e.g., having from 6 to 24 carbon atoms, or from 6 to 16carbon atoms), and/or aralkyl groups (i.e., alkyl with an arylsubstituent, e.g., having from 6 to 24 carbon atoms, or from 6 to 16carbon atoms). Also, any of the functional groups or hydrocarbyl groupsubstituents may be further substituted (if the group permits) with oneor more additional functional groups or hydrocarbyl groups.

Nonlimiting examples of compounds satisfying the above formulae includeheteroatom containing substrates, and heteroatom containing buildingblocks, both of which are described in more detail below.

Heteroatom Containing Substrates As discussed above, transitionmetal-catalyzed allylic alkylation can be used for the enantioselectivepreparation of chiral substances. According to embodiments of thepresent invention, heteroatom containing substrates useful in thetransition metal-catalyzed allylic alkylation reaction include cyclicand acyclic heteroatom containing compounds represented by Formula 1.

In Formula 1, Q is a heteroatom, for example, N, O, P, S or a halogensuch as Cl, I, Br or F. In some embodiments, for example, Q is N or O.Each of R1 through R10 is independently selected from hydrogen,substituted or unsubstituted hydrocarbyl groups, substituted orunsubstituted heteroatom containing hydrocarbyl groups, or functionalgroups. However, in some embodiments, R3 is not hydrogen. In someembodiments, in which R8 and R9 combine to form a carbonyl group (asdiscussed below), R3 is also not phenyl or substituted phenyl. In yetother embodiments, in which R8 and R9 combine to form a carbonyl group(as discussed below), R3 is not a simple carbonyl group. However, insome embodiments, in which R8 and R9 combine to form a carbonyl group(as discussed below), R3 may be a substituted carbonyl group, e.g., acarbonyl group substituted hydrocarbyl group or heteroatom containinghydrocarbyl group or functional group. In some embodiments, though, R3does not include any carbonyl groups, whether substituted orunsubstituted. In yet other embodiments, in which R8 and R9 combine toform a carbonyl group (as discussed below), R3 is not an ethyl group.However, in some embodiments, R3 may be a substituted ethyl group, andR3 may be any other alkyl group (or other group as described above). Insome embodiments, though, R3 is not an ethyl group or a substitutedethyl group. Also, in some embodiments, the carbon atom to which the R3group is attached is a chiral, stereogenic center, i.e., R3 and Y arenot the same.

Y may be selected from hydrogen, heteroatoms, substituted orunsubstituted hydrocarbyl groups, substituted or unsubstitutedheteroatom containing hydrocarbyl groups, or functional groups.Additionally, any two or more adjacent R and Y groups can optionallycombine to form a carbonyl group on the underlying atom. For example, insome embodiments, R8 and R9 combine to form a carbonyl group, as shownin the below Formula 1(a).

Also, any two or more adjacent R and Y groups can optionally combine toform a ring, e.g., a cyclic, heterocyclic, aryl or heteroaryl ring.Indeed, in some embodiments, although Formula 1 depicts an acyclicheteroatom containing compound, Formula 1 also encompasses cyclic,heterocyclic, aryl and heteroaryl compounds. Also, in some embodiments,while R6 and R10 may combine to form nearly any ring structure, R6 andR10 do not form a substituted or unsubstituted benzene ring. In someembodiments, R6 and R10 do not form any aromatic ring. Similarly, insome embodiments, while R4and R6 may combine to form nearly any ringstructure, R4 and R6 do not form a substituted or unsubstituted benzenering. In some embodiments, R4 and R6 do not form any aromatic ring.

In embodiments in which R2 and Y combine to form a ring, in someembodiments, the atom in the ring directly adjacent the Q atom (i.e.,the atom on the opposite side of the Q atom to the carbon atom carryingthe R8 and R9 groups) is not a chiral center. More specifically, any substituents on that atom are the same as each other, and that atom doesnot include two different substituents.

For example, in some embodiments, the R2 group on the Q atom, and the Ygroup combine to form a ring with the Q atom, the carbon atom to whichthe Y group is attached, and the intervening carbon atom. The ringformed between the R2 group and the Y group can be any type of ring withany number of ring atoms. However, the ring formed from the combinationof R2 and Y does not form a benzene ring or ortho-disubstituted benzenering. In some embodiments, though, R2 and Y may form other substitutedbenzene rings. In other embodiments, however, R2 and Y do not form anykind of benzene ring.

In some exemplary embodiments, for example, the ring formed between theR2 group and the Y group may include one or more additional heteroatoms(i.e., additional to the Q atom depicted in Formula 1). In theseembodiments, the compounds of Formula 1 may be represented by Formula 2,below.

In Formula 2, R1 through R10 are the same as defined above with respectto Formula 1. Each of Q1 and Q2 are as defined above with respect to Q1,and are each independently selected from heteroatoms, e.g., N, O, S, Por halogens, such as Cl, I, F or Br. In some embodiments, for example,each of Q1 and Q2 is independently selected from N or O. Additionally,similar to that described above with respect to Formulae 1 and 1(a), anytwo or more adjacent R groups can optionally combine to form a carbonylgroup on the underlying atom. For example, in some embodiments, R8 andR9 combine to form a carbonyl group, as shown in the below Formula 2(a).

Also, in Formula 2, each of x, n and m can be any integer of 0 orgreater. When x is greater than 1, the plurality of Q2 heteroatoms maybe the same as or different from each other. In some embodiments, forexample, each of x, n and m is independently 0, 1, 2, 3 or 4. In someexemplary embodiments, when x and n are both 0, m may be 1, 2, 3 or 4.Conversely, when x and m are both 0, n may be 1, 2, 3 or 4. Theseconfigurations yield compounds having the Formulae 2(b) or 2(c) (whereR8 and R9 combine to form a carbonyl group) below. Also, while m and nare defined here such that the ring depicted in Formula 2 has up to 7ring atoms, it is understood that the size of the ring in Formula 2 isnot particularly limited, and n and m can be any integers correspondingto any ring size. For example, in some embodiments, n and m are integerssuch that the resulting ring depicted in Formula 2 has from 3 to 12 ringatoms. In some embodiments for example, n and m are integers such thatthe resulting ring has from 3 to 10 ring atoms. In other embodiments, nand m are integers such that the resulting ring has from 5 to 7 ringatoms.

Alternatively, in some embodiments, when x is 1, n and m may be anyinteger from 0 to 4 such that the sum of n and m may be 0, 1, 2 or 3.For example, in some embodiments, when x is 1, n may be 0 and m may be0, 1, 2 or 3. In other embodiments, when x is 1, n may be 1 and m may be0, 1 or 2. In still other embodiments, when x is 1, n may be 2 and m maybe 0 or 1. In yet other embodiments, when x is 1, n may be 3 and m maybe 0. Conversely, in some embodiments, when x is 1, m may be 0 and n maybe 0, 1, 2 or 3. In other embodiments, when x is 1, m may be 1 and n maybe 0, 1 or 2. In still other embodiments, when x is 1, m may be 2 and nmay be 0 or 1. In yet other embodiments, when x is 1, m may be 3 and nmay be 0. These configurations yield compounds of Formula 2 in whichthere are two heteroatoms, and cover all configurations of the twoheteroatoms. Specifically, these configurations cover every possibleposition of the second heteroatom (Q2) on the ring depicted in Formula2. Also, while m and n are defined here such that the ring depicted inFormula 2 has up to 7 ring atoms, it is understood that the size of thering in Formula 2 is not particularly limited, and n and m can be anyintegers corresponding to any ring size, as discussed above. Forexample, in some embodiments, n and m are integers such that theresulting ring depicted in Formula 2 has from 3 to 12 ring atoms, forexample 3 to 10 ring atoms or 5 to 7 ring atoms.

In some embodiments, the ring may include the Q atom depicted inFormulae 1 and 2 as the only heteroatom, and include any number ofadditional carbon atoms in the ring. Alternatively, however, the ringdepicted in Formulae 2 and 2(a) through 2(c) can have any number ofheteroatoms positioned anywhere on the ring. For example, as shown inFormula 2 and 2(a) above, the ring may include the heteroatom depictedin Formulae 1 and 2 separated from a group of one or more additionalheteroatoms by one or more carbon atoms, or the ring may include two ormore heteroatoms that are adjacent each other within the ring. However,according to other embodiments, the ring depicted in Formula 2 mayinclude three or more heteroatoms which may be adjacent one another orseparated from each other by at least one carbon atom. Thisconfiguration is depicted in Formulae 2(d) and 2(e) (where R8 and R9combine to form a carbonyl group) below.

In Formula 2(d) and 2(e), each of Q1, Q2 and Q3 is as defined above withrespect to Q1, and are each independently a heteroatom, for example, O,N, S, P, or a halogen such as Cl, I, Br or F. Each of R1 through R10 isalso as described above with respect to Formulae 1, 2 and 2(a) through2(c). Each of a, b and c is independently an integer of 0 or greater. Insome exemplary embodiments, each of a, b and c may be independently aninteger of 0, 1 or 2. For example, in some embodiments, each of a, b andc is 0, yielding a five membered ring including three adjacentheteroatoms. In other embodiments, a is 1 and b and c are both 0,yielding a six membered ring in which Q2 and Q3 are adjacent one anotherand Q2 is separated from Q1 by a carbon atom. In still otherembodiments, a is 2 and b and c are both 0, yielding a seven memberedring in which Q2 and Q3 are adjacent one another and Q2 is separatedfrom Q1 by two carbon atoms.

According to other embodiments, b is 1 and a and c are both 0, yieldinga six membered ring in which Q1 and Q2 are adjacent one another and Q2is separated from Q3 by a carbon atom. In still other embodiments, b is2 and a and c are both 0, yielding a seven membered ring in which Q1 andQ2 are adjacent one another and Q2 is separated from Q3 by two carbonatoms.

In other embodiments, c is 1 and a and b are both 0, yielding a sixmembered ring in which Q1, Q2 and Q3 are adjacent one another. In stillother embodiments, c is 2 and a and b are both 0, yielding a sevenmembered ring in which Q1, Q2 and Q3 are adjacent one another. Also,while a, b and c are defined here such that the ring depicted inFormulae 2, 2(d) and 2(e) has up to 7 ring atoms, it is understood thatthe size of the ring in Formulae 2, 2(d) and 2(e) is not particularlylimited, and a, b and c can be any integers corresponding to any ringsize, as discussed above. For example, in some embodiments, a, b and care integers such that the resulting ring depicted in Formulae 2, 2(d)and 2(e) has from 3 to 12 ring atoms, for example 3 to 10 ring atoms or5 to 7 ring atoms.

In some exemplary embodiments, the ring depicted in Formula 2 mayinclude four heteroatoms, and the four heteroatoms may be placed on thering in any manner. For example, some of the heteroatoms may be spacedfrom each other by one or more ring carbon atoms while others areadjacent, or all heteroatoms may be adjacent each other, or allheteroatoms may be spaced from each other by one or more ring carbonatoms.

Additionally, although the rings discussed above are depicted anddescribed as fully saturated, according to some embodiments of thepresent invention, any of the rings may be unsaturated (i.e., mono- orpoly-unsaturated). To account for these compounds, the heteroatomcontaining substrate of Formula 1 may be represented by Formulae 3 or3(a) (where R8 and R9 combine to form a carbonyl group) below.

In Formulae 3 and 3(a), Q1 and R1 through R10 are as defined above withrespect to Formulae 1, 2 and 2(a) through 2(e). Each of A, B and D isindependently a carbon atom or a heteroatom. However, in someembodiments, in which d is 1 or greater, the A atom located directlyadjacent the Q1 atom is not a chiral center. More specifically, the Raand Rb substituents on that atom are the same as each other, and are nottwo different substituents. Also, the ring formed from Q1, A, B and D isnot a benzene ring or an ortho-disubstituted benzene ring. In someembodiments, though, the ring may be any other substituted benzene ring.In other embodiments, however, the ring is not any kind of benzene ring.

Each of Ra, Rb, R, Rd, Re and Rf may be independently selected fromhydrogen atoms, substituted or unsubstituted hydrocarbyl groups,substituted or unsubstituted heteroatom containing hydrocarbyl groups,halogens or functional groups. However, as discussed above, in someembodiments, in which d is greater than 1, the A atom located directlyadjacent the Q1 atom is not a chiral center, and the Ra and Rbsubstituents on that atom are the same as each other. In someembodiments, however, one R group on each of two adjacent ring atoms cancombine to form a bond, thereby creating a double bond within the ringstructure. Specifically, each of Ra through Rf is either: independentlyhydrogen, a substituted or unsubstituted hydrocarbyl group, asubstituted or unsubstituted heteroatom containing hydrocarbyl group, ora functional group; or combines with another of Ra through Rf to form adouble bond. For example, R1 and one of the Ra groups may combine toform a double bond, one of the Rb groups and one of the Rc groups maycombine to form a double bond within the ring, or one of the Rd groupsand one of the Re groups may combine to form a double bond within thering. Any number of double bonds may be formed within the ringstructure, and the ring structure may be heteroaryl in nature.Alternatively or additionally, two adjacent R groups on the same ringatom (e.g., Ra and Rb, or Rc and Rd, or Re and Rf) can combine to form acarbonyl group on the ring atom. Each of d, e and f is independently aninteger of 0 or greater, for example, an integer of 0, 1, 2, 3, or 4.When d, e or f is greater than 1, the plurality of A, B or D atoms, andthe plurality of Ra, Rb, Rc, Rd, Re or Rf groups may be the same as ordifferent from each other. Also, although Formulae 3 and 3(a) abovedepict a six membered ring, it is understood from the definitions of d,e and f that the ring is not limited to six members, and can have anynumber of ring atoms, as discussed above with respect to Formulae 1, 2and 2(a) through 2(e). Indeed, in some embodiments, the ring has from 3to 12 ring atoms, for example 3 to 10 ring atoms or 5 to 7 ring atoms.

Also, in the rings discussed above, any of the ring atoms, whethercarbon or heteroatom, can be substituted with a substituted orunsubstituted hydrocarbyl group, substituted or unsubstituted heteroatomcontaining hydrocarbyl group, a halogen or a functional group. Indeed,although the rings depicted in Formulae 2 and 2(a) through 2(e) aboveare depicted with hydrogen atoms on each of the ring atoms, any or allof the hydrogen atoms on any or all of the ring atoms may be substitutedwith the substituents described above. As shown in Formula 3, forexample, each of the ring atoms (Q1, A, B and/or D) may include R groupsthat can be hydrogen, a substituted or unsubstituted hydrocarbyl group,a substituted or unsubstituted heteroatom containing hydrocarbyl group,a halogen or a functional group.

In Formulae 1, 1(a), 2, 2(a) through 2(b), 3 and 3(a) above, theheteroatom containing substrates are depicted and described as includinga terminal alkenyl group. This position of the alkenyl group may beimportant for the palladium catalyzed decarboxylative alkylationreaction used to create the building blocks described below. However,for other uses of the heteroatom containing substrates described here(e.g., as reactants in other reactions), the alkenyl group need not bepositioned at the terminal end of the compound. Instead, the alkenylgroup can be positioned elsewhere in the compound. For example, thealkenyl group can be positioned as shown in the below Formulae 1(b) and1(c) (where R8 and R9 combine to form a carbonyl group).

In Formula 1(a), Q, Y and R1 through R10 are as described above withrespect to Formulae 1, 2, 2(a), 2(b) and 3. Also, R11 is selected fromthe same substituents described above for R1 through R9. Specifically,each of R1 through R10 may be independently selected from hydrogen,substituted or unsubstituted hydrocarbyl groups, substituted orunsubstituted heteroatom containing hydrocarbyl groups, halogens orfunctional groups.

In Formulae 1 through 3 above, the terminal alkenyl group can be reacted(e.g., hydrogenated) to make a corresponding alkyl derivative having thebelow Formula 1(d) and 1(e) (in which the R8 and R9 groups combine toform a carbonyl group, and in which z is 0.

In Formula 1(d) and 1(e), Q, Y and R1 through R11 are as described abovewith respect to Formulae A through C. Also, R′ and R″ are independentlyselected from the same substituents described above for R1 through R11.Specifically, each of R1 through R11 and R′ and R″ may be independentlyselected from hydrogen, substituted or unsubstituted hydrocarbyl groups,substituted or unsubstituted heteroatom containing hydrocarbyl groups,halogens or functional groups. Also, it is understood that althoughFormula 1 through 3 are discussed and depicted above as including theterminal alkenyl group, any of those formulae may instead include theterminal alkyl discussed here and depicted in Formulae 1(d) and 1(e).

In some embodiments of the present invention in which the heteroatom isa nitrogen atom, the R group on the heteroatom (i.e., Q, Q1, Q2, Q3, orother heteroatoms in the substrates of Formulae 1 through 3) can be anamine protecting group. Those of ordinary skill in the art would readilyunderstand what is meant by “amine protecting group.” However, somenonlimiting examples of suitable amine protecting groups includecarbobenzyloxy (Cbz) groups, p-methoxybenzyl carbonyl (Moz or MeOZ)groups, tent-butyloxycarbonyl (BOC) groups, fluorenylmethyloxycarbonyl(FMOC) groups, acetyl (Ac) groups, benzoyl (Bz) groups, benzyl (Bn)groups, carbamate groups, p-methoxybenzyl (PMB) groups, dimethoxybenzyl(DMPM) groups, p-methoxyphenyl (PMP) groups, tosyl (Ts) groups,sulfonamide (Nosyl & Nps) groups, methoxybenzoyl groups (OMe-Bz), andfluorobenzoyl groups (F-Bz). For example, in some embodiments, the amineprotecting group is selected from tosyl groups (Ts), butyloxycarbonylgroups (BOC), carbobenzyloxy groups (Cbz), fluoreneylmethyloxycarbonylgroups (FMOC), acetyl groups (Ac), methoxybenzoyl groups (OMe-Bz),fluorobenzoyl groups (F-Bz), and benzoyl groups (Bz).

Also, the substrate compounds are generally racemic, i.e., an equimolarmixture of the (+) and (−) enantiomers of the compound. However, in someembodiments, the substrates may be enantioenriched compounds in whichone of the (+) or (−) enantiomers is present in an enantiomeric excess.Indeed, as used herein, the term “enantionriched” refers to anenantiomeric excess of the particular enantiomer of the compound.Specifically, the substrate compounds according to some embodiments ofthe present invention include on eof (+) or (−) enantiomers in anenantiomeric excess, thus creating an “enantioenriched” substratecompound. In some embodiments, for example, the enantioenrichedsubstrate compound may include one of the (+) or (−) enantiomers in anenantiomeric excess of greater than 50%, for example, about 60% orgreater, or about 70% or greater, or about 80%. or greater According tosome embodiments, the enantioenriched substrate compound may include oneof the (+) or (−) enantiomers in an enantiomeric excess of about 90% orgreater. In other embodiments, the enantioenriched substrate compoundmay include one of the (+) or (−) enantiomers in an enantiomeric excessof about 90% to about 99%.

Some nonlimiting examples of substrates satisfying the above formulae,according to embodiments of the present invention, include the compoundsdepicted below. It is understood that although some of the nitrogenatoms in some of the nitrogen containing-compounds listed below includeprotecting groups, the nitrogen atoms do not necessarily include aprotecting group. Indeed, in some embodiments of the present invention,a hydrogen atom is attached to the nitrogen atom. In each of theexamples listed below, the protecting group on any of the nitrogen atomscan be replaced with a hydrogen atom.

Heteroatom Containing Building Blocks

The heteroatom containing substrates described above may be used tocreate novel building block compounds useful in the formation ofnumerous other chemical and pharmaceutical compounds. Indeed, the novelsubstrates discussed above are designed to create the novel buildingblocks discussed here via palladium-catalyzed decarboxylative alkylationreactions. These reactions, when performed on racemic compositions ofthe substrates described above yield enantioenriched compositions of thebuilding block compounds. As the building blocks discussed here are theresult of palladium-catalyzed decarboxylative alkylation of thesubstrates discussed above, the structures of these compounds aresimilar in many respects to their corresponding substrates. However, aswould be recognized by those of ordinary skill in the art based on thedifferences in the structures, the stereochemistry, enantioselectivityand chemical and physical properties of the building blocks can besignificantly different from those of their corresponding substrates.

According to embodiments of the present invention, heteroatom containingbuilding blocks useful in the creation of target compounds includecyclic and acyclic heteroatom containing building blocks represented byFormula 4.

In Formula 4, as in Formula 1 (of the counterpart heteroatom containingsubstrates), Q is a heteroatom, for example, N, O, P, S or a halogensuch as Cl, I, Br or F. In some embodiments, for example, Q is N or O.Each of R1 through R10 is independently selected from hydrogen,substituted or unsubstituted hydrocarbyl groups, substituted orunsubstituted heteroatom containing hydrocarbyl groups, or functionalgroups. However, in some embodiments, R3 is not hydrogen. In someembodiments, in which z is 0 and R8 and R9 combine to form a carbonylgroup, R3 is also not phenyl or substituted phenyl. In yet otherembodiments, in which z is 0 and R8 and R9 combine to form a carbonylgroup, R3 is not a simple carbonyl group. However, in some embodiments,R3 may be a substituted carbonyl group, e.g., a carbonyl groupsubstituted hydrocarbyl group or heteroatom containing hydrocarbyl groupor functional group. In some embodiments, though, R3 does not includeany carbonyl groups, whether substituted or unsubstituted. In yet otherembodiments, in which z is 0 and R8 and R9 combine to form a carbonylgroup, R3 is not an ethyl group. However, in some embodiments, R3 may bea substituted ethyl group, and R3 may be any other alkyl group (or othergroup as described above). In some embodiments, though, R3 is not anethyl group or a substituted ethyl group. Also, in some embodiments, thecarbon atom to which the R3 group is attached is a chiral, stereogeniccenter, i.e., R3 and Y are not the same.

Y may be selected from hydrogen, heteroatoms, substituted orunsubstituted hydrocarbyl groups, substituted or unsubstitutedheteroatom containing hydrocarbyl groups, or functional groups.Additionally, any two or more adjacent R and Y groups can optionallycombine to form a carbonyl group on the underlying atom. For example, insome embodiments, R8 and R9 combine to form a carbonyl group, as shownin the below Formula 4(a).

Also, any two or more adjacent R and Y groups can optionally combine toform a ring, e.g., a cyclic, heterocyclic, aryl or heteroaryl ring.Indeed, in some embodiments, although Formula 4 depicts an acyclicheteroatom containing compound, Formula 4 also encompass cyclic,heterocyclic, aryl and heteroaryl compounds. Also, in some embodiments,while R6 and R10 may combine to form nearly any ring structure, R6 andR10 do not form a substituted or unsubstituted benzene ring. In someembodiments, R6 and R10 do not form any aromatic ring. Similarly, insome embodiments, while R4 and R6 may combine to form nearly any ringstructure, R4 and R6 do not form a substituted or unsubstituted benzenering. In some embodiments, R4 and R6 do not form any aromatic ring.

In embodiments in which R2 and Y combine to form a ring, in someembodiments, the atom in the ring directly adjacent the Q atom (i.e.,the atom on the opposite side of the Q atom to the carbon atom carryingthe R8 and R9 groups) is not a chiral center. More specifically, any substituents on that atom are the same as each other, and that atom doesnot include two different substituents.

For example, in some embodiments, the R2 group on the Q atom, and the Ygroup combine to form a ring with the Q atom, the carbon atom to whichthe Y group is attached, and the intervening carbon atom. The ringformed between the R2 group and the Y group can be any type of ring withany number of ring atoms. However, the ring formed from the combinationof R2 and Y does not form a benzene ring or ortho-disubstituted benzenering. In some embodiments, though, R2 and Y may form other substitutedbenzene rings. In other embodiments, however, R2 and Y do not form anykind of benzene ring.

In some exemplary embodiments, for example, the ring formed between theR₂ group and the Y group may include one or more additional heteroatoms(i.e., additional to the Q atom depicted in Formula 4). In theseembodiments, the compounds of Formula 4 may be represented by Formula 5,below.

In Formula 5, R1 through R10 are the same as defined above with respectto Formula 4. Each of Q1 and Q2 are as defined above with respect to Q1,and are each independently selected from heteroatoms, e.g., N, O, S, Por halogens, such as Cl, I, F or Br. In some embodiments, for example,each of Q1 and Q2 is independently selected from N or O. Additionally,similar to that described above with respect to Formulae 4 and 4(a), anytwo or more adjacent R groups can optionally combine to form a carbonylgroup on the underlying atom. For example, in some embodiments, R8 andR9 combine to form a carbonyl group, as shown in the below Formula 5(a).

Also, in Formula 5, each of x, n and m can be any integer of 0 orgreater. When x is greater than 1, the plurality of Q2 heteroatoms maybe the same as or different from each other. In some embodiments, forexample, each of x, n and m is independently 0, 1, 2, 3 or 4. In someexemplary embodiments, when x and n are both 0, m may be 1 , 2, 3 or 4.Conversely, when x and m are both 0, n may be 1, 2, 3 or 4. Theseconfigurations yield compounds having the Formulae 5(b) or 5(c) (whereR8 and R9 combine to form a carbonyl group) below. Also, while m and nare defined here such that the ring depicted in Formula 5 has up to 7ring atoms, it is understood that the size of the ring in Formula 5 isnot particularly limited, and n and m can be any integers correspondingto any ring size. For example, in some embodiments, n and m are integerssuch that the resulting ring depicted in Formula 5 has from 3 to 12 ringatoms. In some embodiments for example, n and m are integers such thatthe resulting ring has from 3 to 10 ring atoms. In other embodiments, nand m are integers such that the resulting ring has from 5 to 7 ringatoms.

Alternatively, in some embodiments, when x is 1, n and m may be anyinteger from 0 to 4 such that the sum of n and m may be 0, 1, 2 or 3.For example, in some embodiments, when x is 1, n may be 0 and m may be0, 1, 2 or 3. In other embodiments, when x is 1, n may be 1 and m may be0, 1 or 2. In still other embodiments, when x is 1, n may be 2 and m maybe 0 or 1. In yet other embodiments, when x is 1, n may be 3 and m maybe 0. Conversely, in some embodiments, when x is 1, m may be 0 and n maybe 0, 1, 2 or 3. In other embodiments, when x is 1, m may be 1 and n maybe 0, 1 or 2. In still other embodiments, when x is 1, m may be 2 and nmay be 0 or 1. In yet other embodiments, when x is 1, m may be 3 and nmay be 0. These configurations yield compounds of Formula 5 in whichthere are two heteroatoms, and cover all configurations of the twoheteroatoms. Specifically, these configurations cover every possibleposition of the second heteroatom (Q2) on the ring depicted in Formula5. Also, while m and n are defined here such that the ring depicted inFormula 5 has up to 7 ring atoms, it is understood that the size of thering in Formula 5 is not particularly limited, and n and m can be anyintegers corresponding to any ring size, as discussed above. Forexample, in some embodiments, n and m are integers such that theresulting ring depicted in Formula 5 has from 3 to 12 ring atoms, forexample 3 to 10 ring atoms or 5 to 7 ring atoms.

In some embodiments, the ring may include the Q atom depicted inFormulae 4 and 5 as the only heteroatom, and include any number ofadditional carbon atoms in the ring. Alternatively, however, the ringdepicted in Formulae 5 and 5(a) through 5(c) can have any number ofheteroatoms positioned anywhere on the ring. For example, as shown inFormula 5 and 5(a) above, the ring may include the heteroatom depictedin Formulae 4 and 5 separated from a group of one or more additionalheteroatoms by one or more carbon atoms, or the ring may include two ormore heteroatoms that are adjacent each other within the ring. However,according to other embodiments, the ring depicted in Formula 5 mayinclude three or more heteroatoms which may be adjacent one another orseparated from each other by at least one carbon atom. Thisconfiguration is depicted in Formulae 5(d) and 5(e) (where R8 and R9combine to form a carbonyl group) below.

In Formula 5(d) and 5(e), each of Q1, Q2 and Q3 is as defined above withrespect to Q1, and each is independently a heteroatom, for example, O,N, S, P, or a halogen such as Cl, I, Br or F. Each of R1 through R10 isalso as described above with respect to Formulae 4, 5 and 5(a) through5(c). Each of a, b and c is independently an integer of 0 or greater. Insome exemplary embodiments, each of a, b and c may be independently aninteger of 0, 1 or 2. For example, in some embodiments, each of a, b andc is 0, yielding a five membered ring including three adjacentheteroatoms. In other embodiments, a is 1 and b and c are both 0,yielding a six membered ring in which Q2 and Q3 are adjacent one anotherand Q2 is separated from Q1 by a carbon atom. In still otherembodiments, a is 2 and b and c are both 0, yielding a seven memberedring in which Q2 and Q3 are adjacent one another and Q2 is separatedfrom Q1 by two carbon atoms.

According to other embodiments, b is 1 and a and c are both 0, yieldinga six membered ring in which Q1 and Q2 are adjacent one another and Q2is separated from Q3 by a carbon atom. In still other embodiments, b is2 and a and c are both 0, yielding a seven membered ring in which Q1 andQ2 are adjacent one another and Q2 is separated from Q3 by two carbonatoms.

In other embodiments, c is 1 and a and b are both 0, yielding a sixmembered ring in which Q1, Q2 and Q3 are adjacent one another. In stillother embodiments, c is 2 and a and b are both 0, yielding a sevenmembered ring in which Q1, Q2 and Q3 are adjacent one another. Also,while a, b and c are defined here such that the ring depicted inFormulae 5, 5(d) and 5(e) has up to 7 ring atoms, it is understood thatthe size of the ring in Formulae 5, 5(d) and 5(e) is not particularlylimited, and a, b and c can be any integers corresponding to any ringsize, as discussed above. For example, in some embodiments, a, b and care integers such that the resulting ring depicted in Formulae 5, 5(d)and 5(e) has from 3 to 12 ring atoms, for example 3 to 10 ring atoms or5 to 7 ring atoms.

In some exemplary embodiments, the ring depicted in Formula 5 mayinclude four heteroatoms, and the four heteroatoms may be placed on thering in any manner. For example, some of the heteroatoms may be spacedfrom each other by one or more ring carbon atoms while others areadjacent, or all heteroatoms may be adjacent each other, or allheteroatoms may be spaced from each other by one or more ring carbonatoms.

Additionally, although the rings discussed above may be depicted anddescribed as fully saturated, according to some embodiments of thepresent invention, any of the rings may be unsaturated (i.e., mono- orpoly-unsaturated). To account for these compounds, the heteroatomcontaining substrate of Formula 4 may be represented by Formulae 6 or6(a) (where R8 and R9 combine to form a carbonyl group) below.

In Formulae 6 and 6(a), Q1 and R1 through R10 are as defined above withrespect to Formulae4, 5 and 5(a) through 5(e). Each of A, B and D isindependently a carbon atom or a heteroatom. However, in someembodiments, in which d is 1 or greater, the A atom located directlyadjacent the Q1 atom is not a chiral center. More specifically, the Raand Rb substituents on that atom are the same as each other, and are nottwo different substituents. Also, the ring formed from Q1, A, B and D isnot a benzene ring or an ortho-disubstituted benzene ring. In someembodiments, though, the ring may be any other substituted benzene ring.In other embodiments, however, the ring is not any kind of benzene ring.

Each of Ra, Rb, Rc, Rd, Re and Rf may be independently selected fromhydrogen atoms, substituted or unsubstituted hydrocarbyl groups,substituted or unsubstituted heteroatom containing hydrocarbyl groups,halogens or functional groups. However, as discussed above, in someembodiments, in which d is greater than 1, the A atom located directlyadjacent the Q1 atom is not a chiral center, and the Ra and Rbsubstituents on that atom are the same as each other. In someembodiments, however, one R group on each of two adjacent ring atoms cancombine to form a bond, thereby creating a double bond within the ringstructure. Specifically, each of Ra through Rf is either: independentlyhydrogen, a substituted or unsubstituted hydrocarbyl group, asubstituted or unsubstituted heteroatom containing hydrocarbyl group, ora functional group; or combines with another of Ra through Rf to form adouble bond. For example, R1 and one of the Ra groups may combine toform a double bond, one of the Rb groups and one of the Rc groups maycombine to form a double bond within the ring, or one of the Rd groupsand one of the Re groups may combine to form a double bond within thering. Any number of double bonds may be formed within the ringstructure, and the ring structure may be heteroaryl in nature.Alternatively or additionally, two adjacent R groups on the same ringatom (e.g., Ra and Rb, or Rc and Rd, or Re and Rf) can combine to form acarbonyl group on the ring atom. Each of d, e and f is independently aninteger of 0 or greater, for example, an integer of 0, 1, 2, 3, or 4.When d, e or f is greater than 1, the plurality of A, B or D atoms, andthe plurality of Ra, Rb, Rc, Rd, Re or Rf groups may be the same as ordifferent from each other. Also, although Formulae 6 and 6(a) abovedepict a six membered ring, it is understood from the definitions of d,e and f that the ring is not limited to six members, and can have anynumber of ring atoms, as discussed above with respect to Formulae 4, 4and 4(a) through 4(e). Indeed, in some embodiments, the ring has from 3to 12 ring atoms, for example 3 to 10 ring atoms or 5 to 7 ring atoms.

Also, in the rings discussed above, any of the ring atoms, whethercarbon or heteroatom, can be substituted with a substituted orunsubstituted hydrocarbyl group, substituted or unsubstituted heteroatomcontaining hydrocarbyl group, a halogen or a functional group. Indeed,although the rings depicted in Formulae 5 and 5(a) through 5(e) aboveare depicted with hydrogen atoms on each of the ring atoms, any or allof the hydrogen atoms on any or all of the ring atoms may be substitutedwith the substituents described above. As shown in Formula 6, forexample, each of the ring atoms (Q1, A, B and/or D) may include R groupsthat can be hydrogen, a substituted or unsubstituted hydrocarbyl group,a substituted or unsubstituted heteroatom containing hydrocarbyl group,a halogen or a functional group.

In some embodiments of the present invention, the building blockcompounds can have an alternate structure represented by the belowFormulae D. The compounds of Formula D include compounds created by thepalladium catalyzed decarboxylative alkylation of substrate compoundsrepresented by Formula 1(a), 2(a) or 3(a) in which Q (or Q1) is O.

As noted above, compounds of Formula D can be made through the palladiumcatalyzed decarboxylative alkylation of a lactone satisfying one ofFormulae 1(a), 2(a) or 3(a) above. Specifically, the compound of FormulaD will result when a compound of Formula 3(a) (in which Q1 is O) issubjected to palladium catalyzed decarboxylative alkylation. In FormulaD, A, B, D, Ra, Rb, Rc, Rd, Re, Rf, R3, R4, R5, R6, R7 and R10 are asdescribed above with respect to Formulae 1 through 3. For example, eachof Ra, Rb, R, Rd, Re and Rf may be independently selected from hydrogenatoms, substituted or unsubstituted hydrocarbyl groups, substituted orunsubstituted heteroatom containing hydrocarbyl groups, halogens orfunctional groups. However, similar to that discussed above with respectto Formulae A through C and 4 through 6, in some embodiments, in which dis 1 or greater, the A atom that is directly adjacent the OH group isnot a chiral center. More specifically, the Ra and Rb groups on the Aatom that is directly adjacent the OH group are the same as each other.In some embodiments, however, one R group on each of two adjacent ringatoms can combine to form a bond, thereby creating a double bond withinthe ring structure. Specifically, each of Ra through Rf is either:independently hydrogen, a substituted or unsubstituted hydrocarbylgroup, a substituted or unsubstituted heteroatom containing hydrocarbylgroup, or a functional group; or combines with another of Ra through Rfto form a double bond. In Formulae 4, 4(a), 5, 5(a) through 5(b), 6 and6(a) above, the heteroatom containing building blocks are depicted anddescribed as including a terminal alkenyl group. This position of thealkenyl group may be imparted by the palladium catalyzed decarboxylativealkylation reaction used to create the building blocks. However, aftercreation via the palladium catalyzed decarboxylative alkylationreaction, the building blocks can be further modified to move thealkenyl group to a position other than the terminal end of the compound.For example, the alkenyl group can be positioned as shown in the belowFormulae 4(b) and 4(c) (where R8 and R9 combine to form a carbonylgroup).

In Formula 4(a), Q, Y and R1 through R10 are as described above withrespect to Formulae 4, 5, 5(a) through 5(e), 6 and 6(a). Also, R11 isselected from the same substituents described above for R1 through R9.Specifically, each of R1 through R11 may be independently selected fromhydrogen, substituted or unsubstituted hydrocarbyl groups, substitutedor unsubstituted heteroatom containing hydrocarbyl groups, halogens orfunctional groups.

In other embodiments, in which the compound is analogous to the compoundrepresented by Formula D, the alkenyl group can be positioned as shownin the below Formula D(i).

In Formula D(i), A, B, D, Ra through Rf, d, e, f, and R3 through R10 areas described above. Also, R11 is selected from the same substituentsdescribed above for R1 through R10. Specifically, each of R1 through R11may be independently selected from hydrogen, substituted orunsubstituted hydrocarbyl groups, substituted or unsubstitutedheteroatom containing hydrocarbyl groups, halogens or functional groups.However, similar to that discussed above with respect to Formulae Athrough C and 4 through 6, in some embodiments, in which d is 1 orgreater, the A atom that is directly adjacent the OH group is not achiral center. More specifically, the Ra and Rb groups on the A atomthat is directly adjacent the OH group are the same as each other. Insome embodiments, however, one R group on each of two adjacent ringatoms can combine to form a bond, thereby creating a double bond withinthe ring structure. Specifically, each of Ra through Rf is either:independently hydrogen, a substituted or unsubstituted hydrocarbylgroup, a substituted or unsubstituted heteroatom containing hydrocarbylgroup, or a functional group; or combines with another of Ra through Rfto form a double bond.

Additionally, in Formulae 4, 4(a), 5, 5(a) through 5(b), 6 and 6(a)above, the heteroatom containing building blocks are depicted anddescribed as potentially including non-hydrogen R groups (R7 and or R10)on the terminal alkenyl group. In embodiments in which the buildingblocks include such a non-hydrogen R group on the terminal alkenylgroup, the R group is added via a reaction occurring after the palladiumcatalyzed decarboxylative alkylation reaction used to create thebuilding block. Specifically, while the palladium catalyzeddecarboxylative alkylation reaction may result in building blocksincluding only hydrogen on the terminal alkenyl, if desired, thebuilding block furnished by the palladium catalyzed decarboxylativealkylation reaction can be further modified to substitute one or both ofthe hydrogen atoms on the terminal alkenyl group with a substituted orunsubstituted hydrocarbyl, a substituted or unsubstituted heteroatomcontaining hydrocarbyl, a halogen or a functional group.

In Formulae 4 through 6 above, the terminal alkenyl group can be reacted(e.g., hydrogenated) to make a corresponding alkyl derivative having thebelow Formula 4(d) and 4(e) (in which the R8 and R9 groups combine toform a carbonyl group) in which z is 0.

In Formula 4(d) and 4(e), Q, Y and R1 through R11 are as described abovewith respect to Formulae A through C. Also, R′ and R″ are independentlyselected from the same substituents described above for R1 through R11.Specifically, each of R1 through R11 and R′ and R″ may be independentlyselected from hydrogen, substituted or unsubstituted hydrocarbyl groups,substituted or unsubstituted heteroatom containing hydrocarbyl groups,halogens or functional groups. Also, it is understood that althoughFormula 4 through 6 are discussed and depicted above as including theterminal alkenyl group, any of those formulae may instead include theterminal alkyl discussed here and depicted in Formulae 4(d) and 4(e).

In some embodiments of the present invention in which the heteroatom isa nitrogen atom, the R group on the heteroatom (i.e., Q, Q1, Q2, Q3, orother heteroatoms in the building blocks of Formulae 4 through 6) can bean amine protecting group. Those of ordinary skill in the art wouldreadily understand what is meant by “amine protecting group.” However,some nonlimiting examples of suitable amine protecting groups includecarbobenzyloxy (Cbz) groups, p-methoxybenzyl carbonyl (Moz or MeOZ)groups, tent-butyloxycarbonyl (BOC) groups, fluorenylmethyloxycarbonyl(FMOC) groups, acetyl (Ac) groups, benzoyl (Bz) groups, benzyl (Bn)groups, carbamate groups, p-methoxybenzyl (PMB) groups, dimethoxybenzyl(DMPM) groups, p-methoxyphenyl (PMP) groups, tosyl (Ts) groups,sulfonamide (Nosyl & Nps) groups, methoxybenzoyl groups (OMe-Bz), andfluorobenzoyl groups (F-Bz). For example, in some embodiments, the amineprotecting group is selected from tosyl groups (Ts), butyloxycarbonylgroups (BOC), carbobenzyloxy groups (Cbz), fluoreneylmethyloxycarbonylgroups (FMOC), acetyl groups (Ac), methoxybenzoyl groups (OMe-Bz),fluorobenzoyl groups (F-Bz), and benzoyl groups (Bz).

In some alternate embodiments, however, the R group(s) on the N can behydrogen, a substituted or unsubstituted hydrocarbyl group, asubstituted or unsubstituted heteroatom containing hydrocarbyl group, ora functional group. For example, in some embodiments, the R group(s) onthe N atom may be H or OH.

Also, the building blocks described above are generally formed from theracemic form of the corresponding substrate compound. The resultingbuilding block compounds may also be racemic, however, in someembodiments, the palladium catalyzed decarboxylative alkylationprocedures result in enantioenriched building block compounds. As usedherein, the term “enantionriched” refers to an enantiomeric excess ofthe particular enantiomer of the compound. Specifically, the buildingblock compounds according to embodiments of the present inventioninclude on eof (+) or (−) enantiomers in an enantiomeric excess, thuscreating an “enantioenriched” building block compound. In someembodiments, for example, the enantioenriched building block compoundmay include one of the (+) or (−) enantiomers in an enantiomeric excessof greater than 50%, for example, about 60% or greater, or about 70% orgreater, or about 80%. or greater According to some embodiments, theenantioenriched building block compound may include one of the (+) or(−) enantiomers in an enantiomeric excess of about 90% or greater. Inother embodiments, the enantioenriched building block compound mayinclude one of the (+) or (−) enantiomers in an enantiomeric excess ofabout 90% to about 99%.

Some nonlimiting examples of building blocks satisfying the aboveformula, according to embodiments of the present invention, include thecompounds depicted below. It is understood that although some of thenitrogen atoms in some of the nitrogen containing-compounds listed belowinclude protecting groups, the nitrogen atoms do not necessarily includeprotecting groups. Indeed, in some embodiments of the present invention,hydrogen atoms are attached to the nitrogen atoms. In each of theexamples listed below, the protecting group on any of the nitrogen atomscan be replaced with a hydrogen atom.

Palladium Catalyzed Decarboxylative Alkylation Reaction

As discussed above, decarboxylative alkylation chemistry, and relatedallylic alkylation methods have been used in the creation of certainclasses of compounds, e. g., α-quaternary ketones.

The building blocks according to embodiments of the present invention,discussed in detail above, can be prepared by the transition metalcatalyzed decarboxylative alkylation processes discussed in thereferences cited above. However, further investigation into the knownketone allylic alkylation reactions (and other related reactions), asdiscussed here, led to increased enantio- and stereo-selectivity of thereaction to yield highly enantioenriched building block compounds.

In the course of investigating the ketone enolate allylic alkylation andother alkylation processes, interesting ligand electronic effects and,in certain cases, pronounced solvent effects were encountered. McDougal,et al., “High-throughput screening of the asymmetric decarboxylativealkylation reaction of enolate-stabilized enol carbonates,” Synlett1712-1716 (2010), the entire content of which is incorporated herein byreference. For example, it was found that for inductively- andresonance-stabilized enolates, highly electron deficient ligands andnon-polar solvents are desired. With these findings as a backdrop,further probing of these subtle effects involved examination of enolatereactivity in a lactam series that would be amenable to both steric andelectronic fine-tuning. This further probing led to ligand and solventdesigns useful for the alkylation of N-heterocycles (and other nitrogencontaining compounds) and the construction of the novel building blockcompounds (discussed above) that are useful for medicinal and polymerchemistry.

Preliminary data suggested that electron rich N-alkyl lactam derivativeswere poor substrates for decarboxylative alkylation due to lowreactivity. Thus, electron withdrawing N-protecting groups were chosen.These substrates were screened across a series of four solvents (THF,MTBE, toluene, and 2:1 hexane-toluene) while employing twoelectronically distinct ligands on Pd. Specifically, the reactions usedin the screening were carried out using racemic lactams 1a through 1h(depicted below) as the reactants, a Pd₂(dba)₃ catalyst (5 mol %), asolvent and a ligand. For each of the lactam compounds la through 1h,eight experiments were carried out. Specifically, four experiments werecarried out using the same first ligand, i.e., (S)-t-BuPHOX (12.5 mol%), but varying the solvent (0.033 M) between THF, MTBE, toluene, and2:1 hexane-toluene. The other four experiments for each lactam compoundwere carried out using the same second ligand, i.e., (S)-(CF3)3-t-BuPHOX(12.5 mol %), but varying the solvent (0.033 M) between THF, MTBE,toluene, and 2:1 hexane-toluene. Each experiment was carried out at 40°C.

The compounds resulting from the palladium catalyzed decarboxylativealkylation reactions of Compounds 1a through 1h, described above, aredepicted below as Compounds 2a through 2h, where Compound 2a correspondsto the compound made from the reaction of Compound 1a, Compound 2bcorresponds to the compound made from the reaction of Compound 1b,Compound 2c corresponds to the compound made from the reaction ofCompound 1c, Compound 2d corresponds to the compound made from thereaction of Compound 1d, Compound 2e corresponds to the compound madefrom the reaction of Compound 1e, Compound 2f corresponds to thecompound made from the reaction of Compound 1f, Compound 2g correspondsto the compound made from the reaction of Compound 1g, and Compound 2hcorresponds to the compound made from the reaction of Compound 1h.

The results of this broad screen were highly encouraging, as shown inFIG. 1 (depicting the enantiomeric excess of the compounds preparedusing the lactam reactants (Compounds 1a through 1h) with the variousligands and solvents discussed above). Reactivity across all substrateswith either ligand was uniformly good, as all of the compounds werecompletely converted to the desired product. Strikingly, as theN-substituent group was changed from sulfonyl to carbamoyl to acylfunctionalities, the enantioselectivity rose from nearly zero to nearlyperfect. There was also a difference between the two ligands, andelectron poor (S)-(CF₃)₃-t-BuPHOX was the better choice. As the solventsystem became less polar, a distinct increase in enantiomeric excess wasobserved, however, this effect was substantially less pronounced forreactions employing the electron poor ligand and for reactions varyingthe N-substituent. Ultimately, with the N-benzoyl group (Bz) on thesubstrate (i.e., Compound 1h) and (S)-(CF₃)₃-t-BuPHOX as ligand, thereaction produced the lactam of Compound 2h in>96% ee in each of thefour solvents.

Given these results, investigation of the reaction scope was performedby exploring a range of substituted N-acyl lactam derivatives. Thesederivatives are shown in Table 1 below.

TABLE 1 a Pd-catalyzed Enantioselective Alkylation

b α-Quaternary δ-Lactams

c Other Ring Sizes and Frameworks

d Other N-acyl Groups

Importantly, reproducing the screening reaction on preparative scalefurnishes the N-Bz piperidinone of Compound 2h in 85% isolated yield and99% ee (see box (b) in Table 1 above). Alteration of the C(α)-group toother alkyl and functionalized alkyl units (e.g., —CH₂CH₃ and —CH₂Ph),as well as to moieties possessing additional acidic protons (e.g.,—CH₂CH₂CO₂Me and —CH₂CH₂CN) leads to high yields of the lactams ofCompounds 3 through 6 (see box b in Table 1 above) in uniformly goodenantioenrichment (99% ee). Common silyl protecting groups are toleratedin the transformation and the lactam of Compound 7 is furnished in 85%yield and 96% ee. Substituted allyl groups can be incorporated, howeveronly at C(2), leading to products such as the methallyl lactam ofCompound 8 and the chloroallyl lactam of Compound 9 in good yield andenantioselectivity (≥95% ee).

Beyond piperidinones, pyrrolidinones and caprolactams are also goodsubstrate classes, furnishing the heterocycles of Compounds 10 through13 (see box c of Table 1 above) in good yield and ee. Additionally, themorpholine-derived product of Compound 14, containing aC(α)-tetrasubstituted tertiary center, is produced in 91% yield and 99%ee. C(a)-Fluoro substitution is readily introduced into the1,3-dicarbonyl starting material and is viable in the enantioselectivereaction leading to the fluoropyrrolidinone of Compound 12 (86% yield,98% ee) and the fluoropiperidinone of Compound 15 (89% yield, 99% ee).Moreover, N-Bz glutarimides serve as good substrates smoothly reactingto provide the cyclic imides of Compounds 16 and 17 in high yield andenantioselectivity. Finally, alteration of the N-Bz group is possible(see box din Table 1 above), giving lactams with an N-acetyl group(Compound 18), N-carbamates (Compounds 19 and 20), and a variety ofN-aroyl derivatives (Compounds 21 through 23).

These screening procedures highlight certain methods according to thepresent invention. In particular, as can be seen from the screeningprocedures described above, according to some embodiments of the presentinvention, modifying the traditional transition metal catalyzeddecarboxylative alkylation reaction by using an electron poor ligandyields enantioenriched compounds. As used herein, the term “electronpoor” is used in its art-recognized sense, and not as a term of degreeor approximation. Indeed, those of ordinary skill in the art wouldreadily understand what is meant by the term “electron poor.” However,in some embodiments, the electron poor ligand may be a (S)-t-BuPHOX inwhich one or more of the hydrogen atoms on the t-Bu moiety issubstituted with a fluorine atom or other electron poor functionalgroup, such as, for example, a partially or fully fluorinatedhydrocarbyl or heteroatom containing hydrocarbyl group, a NO₂ group, ora SO₂R group (in which R in SO₂R is any substituted or unsubstitutedhydrocarbyl, heteroatom containing hydrocarbyl, or functional group). Insome embodiments, for example, the t-Bu moiety may be replaced, yieldinga R′—PHOX (e.g., a (S)—R′—PHOX) ligand, in which R′ may be a partiallyor fully fluorinated hydrocarbyl or heteroatom containing hydrocarbylgroup, a NO₂ group, a SO₂R group (in which R in SO₂R is any substitutedor unsubstituted hydrocarbyl, heteroatom containing hydrocarbyl, orfunctional group), or a hydrocarbyl or heteroatom containing hydrocarbylgroup in which at least one of the hydrogen atoms is replaced by anelectron poor group, such as, for example, a fluorine atom, a NO₂ group,or a SO₂R group (in which R in SO₂R is any substituted or unsubstitutedhydrocarbyl, heteroatom containing hydrocarbyl, or functional group.

Accordingly, in some embodiments of the present invention, a method ofpreparing an enantioenriched heteroatom containing building blockcompound includes reaction of a heteroatom containing substrate compoundwith a palladium-based catalyst and an electron poor ligand in thepresence of a solvent. The electron poor ligand is as described above,and the palladium catalyst is not particularly limited, and those ofordinary skill in the art would be able to select a suitable catalyst.However, nonlimiting examples of suitable catalysts include Pd₂(dba)₃and Pd₂(pmdba)₃ (dba=dibenzylidene acetone;pmdba=di(p-methoxybenzylidene) acetone). The solvent is also notparticularly limited, and can be any solvent normally used in metalcatalyzed decarboxylative alkylation procedures. Some nonlimitingexamples of suitable solvents include THF, MTBE, toluene, andhexane:toluene (2:1). Additional ligands, catalysts and solvents usefulin the reactions according to embodiments of the present invention, andadditional reaction particulars, are disclosed in U.S. Pat. No.7,235,698 to Behenna, et al., the entire content of which isincorporated herein by reference.

The enantioenriched products formed by the catalytic asymmetricalkylation chemistry according to embodiments of the present inventioncan be of broad utility in synthetic chemistry. To illustrate thispoint, the lactam of Compound 3 can be transformed into the Aspidospermaalkaloid (+)-quebrachamine by modification of a previous route thatemployed a chiral auxiliary. See Amat, et al., “EnantioselectiveSynthesis of 3,3-Disubstituted Piperidine Derivatives by EnolateDialkylation of Phenylglycinol-Derived Oxazolopiperidone Lactams,” J.Org. Chem. 72, 4431-4439 (2007), the entire content of which isincorporated herein by reference. Additionally, cleavage of the N-Bzgroup of the lactam of Compound 3 produces the chiral lactam of Compound24, a compound previously used as a racemate in the synthesis ofrhazinilam, a microtubule-disrupting agent that displays similarcellular characteristics to paclitaxel. Edler, et al., “Demonstration ofmicrotubule-like structures formed with (−)-rhazinilam from purifiedtubulin outside of cells and a simple tubulin-based assay for evaluationof analog activity,” Arch. Biochem. and Biophys. 487, 98-104 (2009);Magnus, et al., “Concise synthesis of (±)-rhazinilam,” Tetrahedron 57,8647-8651 (2001), the entire contents of both of which are incorporatedherein by reference. The below Synthesis Reaction Scheme depicts routesto the (+)-Quebrachamine and (+)-Rhazinilam. Finally, reduction of thelactam of Compound 24 produces the C(3)-quaternary piperidine ofCompound 25 and demonstrates access to the corresponding amine buildingblocks.

Synthesis Reaction Scheme

In summary, embodiments of the present invention are directed tosubstrates useful in preparing enantioenriched quaternary N-containingcompounds, and other embodiments are directed to the enantioenrichedquaternary N-containing compounds. Additionally, embodiments of thepresent invention are directed to methods for the catalyticenantioselective alkylation of nitrogen containing derivatives (e.g.,monocyclic 5-, 6-, and 7-membered lactam enolate derivatives) to formquaternary N-containing compounds (e.g., α-quaternary anda-tetrasubstituted tertiary lactams). The reaction discovery process wasenabled by parallel screening of reaction parameters and led to theidentification of a sterically and electronically tuned system forhighly enantioselective alkylation. This method has been applied to thecatalytic asymmetric synthesis of key intermediates previously employedfor the construction of Aspidosperma alkaloids. Finally, the asymmetricproducts formed according to embodiments of the present invention arewidely useful as building blocks for the preparation of a wide range ofnitrogen containing compounds (including heterocycles) prevalent inmaterials science, medicinal chemistry and natural products.

Experimental

The following examples and experimental procedures are presented forillustrative purposes only, and do not limit the scope of the presentinvention. In the examples below and description throughout, certainterms are used as shorthand. The shorthand terms are known to those ofordinary skill in the art, however, the following Terms Table lists theshorthand used and its corresponding meaning.

Terms Table Shorthand Meaning Ts Tosyl Boc Tert-butyloxy carbonyl groupCbz Carboxy benzyl group Fmoc Fluorenyl methyloxy carbonyl group AcAcetyl group 4-OMe-Bz 4-methoxy-benzoyl group 4-F-Bz 4-fluoro-benzoylgroup Bz Benzoyl group THF Tetrahydrofuran MTBE Methyl tert-butyl etherTol Toluene Hex:Tol Mixed hexane and toluene solvent Ph Phenyl group OPh(or PhO) Phenyloxy group

Materials and Methods

Unless otherwise stated, reactions were performed in flame-driedglassware under an argon or nitrogen atmosphere using dry, deoxygenatedsolvents. Solvents were dried by passage through an activated aluminacolumn under argon. Brine solutions are saturated aqueous sodiumchloride solutions. Tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃)was purchased from Strem and stored in a glove box. Lithiumbis(trimethylsilyl)amide was purchased from Aldrich and stored in aglove box. Tris[bis(p-methoxybenzylidene)-acetone]dipalladium(0)(Pd₂(pmdba)₃) was prepared by known methods and stored in a glovebox.See McDougal, et al., “High-throughput screening of the asymmetricdecarboxylative alkylation reaction of enolate-stabilized enolcarbonates, ”Synlett 1712-1716. (2010), the entire content of which hasalready been incorporated herein by reference. (S)-t-BuPHOX,(S)-(CF₃)₃-t-BuPHOX, and allyl cyanoformate were prepared by knownmethods. See Helmchen, et al., “Phosphinooxazolines—a new class ofversatile, modular P,N-ligands for asymmetric catalysis,” Acc. Chem.Res. 33, 336-345 (2000); Tani, et al., “A facile and modular synthesisof phosphinooxazoline ligands,” Org. Lett. 9, 2529-2531 (2007);McDougal, et al., “Rapid synthesis of an electron-deficient t-BuPHOXligand: cross-coupling of aryl bromides with secondary phosphineoxides,” Tetrahedron Lett. 51, 5550-5554 (2010), the entire contents ofall of which have already been incorporated herein by reference.

Selectfluor, methyl iodide, and ethyl iodide were purchased fromAldrich, Acros Organics, Strem, or Alfa Aesar and used as receivedunless otherwise stated. Sodium hydride (NaH) was purchased as a 60%dispersion in mineral oil from Acros and used as such unless otherwisestated. Triethylamine was distilled from CaH2 prior to use. Acrolein,acrylonitrile, methyl acrylate, and benzoyl chloride were distilledprior to use.

Reaction temperatures were controlled by an IKAmag temperaturemodulator. Thin-layer chromatography (TLC) was performed using E. Mercksilica gel 60 F254 precoated plates (0.25 mm) and visualized by UVfluorescence quenching, anisaldehyde, KMnO₄, or CAM staining. ICN Silicagel (particle size 0.032-0.063 mm) was used for flash chromatography.Analytical chiral HPLC was performed with an Agilent 1100 Series HPLCutilizing a Chiralpak (AD-H or AS) or Chiralcel (OD-H, OJ-H, or OB-H)columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd.with visualization at 220 or 254 nm. Analytical chiral SFC was performedwith a JACSO 2000 series instrument utilizing Chiralpak (AD-H or AS-H)or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.6 mm x 25 cm), or aChiralpak IC column (4.6 mm x 10 cm) obtained from Daicel ChemicalIndustries, Ltd with visualization at 210 or 254 nm. Optical rotationswere measured with a Jasco P-2000 polarimeter at 589 nm.

¹H and ¹³C NMR spectra were recorded on a Varian Inova 500 (at 500 MHzand 126 MHz, respectively) or a Mercury 300 (at 300 MHz and 75 MHz,respectively), and are reported relative to residual protio solvent(CDCl₃=7.26 and 77.0 ppm and C₆D₆=7.16 and 128.0 ppm, respectively).Data for ¹H NMR spectra are reported as follows: chemical shift (δppm)(multiplicity, coupling constant (Hz), integration). IR spectra wererecorded on a Perkin Elmer Paragon 1000 spectrometer and are reported infrequency of absorption (cm⁻¹). High resolution mass spectra wereobtained using an Agilent 6200 Series TOF with an Agilent G1978AMultimode source in electrospray ionization (ESI), atmospheric pressurechemical ionization (APCI) or mixed (MM) ionization mode or from theCaltech Mass Spectral Facility.

Preparation of Substrates for the Ligand, Protecting Group and SolventScreening The reactions used to probe the ligand, protecting group andsolvent effects (discussed above) involved preparing a collection ofracemic lactam substrates (i.e., Compounds 1a through 1h satisfying theformula for Compound 1, depicted below) for palladium-catalyzeddecarboxylative allylic alkylation, and screening these substrates forreactivity and enantioselectivity across an array of solvents employingtwo chiral ligands, (S)-t-BuPHOX and (S)-(CF₃)₃-t-BuPHOX. For adescription of the structure and synthesis of these ligands, seeHelmchen, et al., “Phosphinooxazolines—a new class of versatile, modularP,N-ligands for asymmetric catalysis,” Acc. Chem. Res. 33, 336-345(2000); Tani, et al., “A facile and modular synthesis ofphosphinooxazoline ligands,” Org. Lett. 9, 2529-2531 (2007); McDougal,et al., “Rapid synthesis of an electron-deficient t-BuPHOX ligand:cross-coupling of aryl bromides with secondary phosphine oxides,”Tetrahedron Lett. 51, 5550-5554 (2010), the entire contents of all ofwhich are incorporated herein by reference. The preparation of thesecompounds, and the screening reactions performed to make theenantioenriched Compounds 2a through 2h are described here.

Compound 1—Generic Formula for Compounds 1a hrough 1h

Some derivatives of Compound 1 (above) were made by a diallyl malonatemethod, i.e., the method represented by the below Diallyl MalonateMethod Reaction Scheme.

In the above Diallyl Malonate Method Reaction Scheme, aldehyde SI2,carbamate SI3, and lactam SI4 were prepared according to the followingprocedures. Also, although the final reaction depicted in the DiallylMalonate Method Reaction Scheme describes the reaction used to formCompound 1h, analogous reactions can be used to form Compounds 1athrough 1g, as also described below.

Aldehyde S12: To a cooled (0° C.) solution of diallyl 2-methylmalonate(SI1)⁵ (17.0 g, 84.7 mmol, 1.00 equiv) and acrolein (6.23 mL, 93.2 mmol,1.10 equiv) in MeCN (282 mL) was added DBU (253 mL, 1.70 mmol, 0.02equiv). After 15 min, the reaction mixture was diluted with saturatedaqueous NH4C1 (200 mL) and EtOAc (100 mL) and the phases were separated.The aqueous phase was extracted with EtOAc (3×200 mL) and the combinedorganic phases were dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The resulting oil was purified by flash chromatography(8×16 cm SiO₂, 10 to 20% EtOAc in hexanes) to afford aldehyde SI2 as acolorless oil (19.7 g, 92% yield). R_(f)=0.32 (20% EtOAc in hexanes); ¹HNMR (300 MHz, CDCl₃) d 9.71 (t, J=1.2 Hz, 1H), 5.83 (ddt, J=17.2, 10.5,5.7 Hz, 2H), 5.26 (dq, J=17.2, 1.5 Hz, 2H), 5.19 (dq, J=10.4, 1.3 Hz,2H), 4.57 (dt, J=5.6, 1.4 Hz, 4H), 2.55-2.45 (m, 2H), 2.20-2.10 (m, 2H),1.41 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) d 200.6, 171.2, 131.3, 118.5,65.9, 52.8, 39.2, 27.7, 20.3; IR (Neat Film NaCl) 2988, 2945, 1732,1230, 1186, 1116, 984, 935 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₁₃H₁₉O₅ [M+H]⁺: 255.1227, found 255.1223.

Carbamate SI3: To a cooled (0° C.) solution of aldehyde SI2 (19.7 g,77.5 mmol, 1.00 equiv), BocNH₂ ⁶ (22.7 g, 194 mmol, 2.50 equiv), andEt₃SiH (31.0 mL, 194 mmol, 2.50 equiv) in MeCN (310 mL) was addedtrifluoroacetic acid (12.1 mL, 163 mmol, 2.10 equiv) dropwise over 5min. The reaction mixture was stirred at 0° C. for 2 h and at ambienttemperature for an additional 18 h, at which point the reaction mixturewas cooled (0° C.), treated with saturated aqueous NaHCO₃ (150 mL),stirred for 40 min, and concentrated under reduced pressure to removeMeCN (˜250 mL). The remaining material was diluted with Et₂O (200 mL)and the phases were separated. The aqueous phase was extracted with Et₂O(4×100 mL) and EtOAc (1×150 mL), and the combined organic phases werewashed with brine (2×150 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting oil was purified byflash chromatography (8×25 cm SiO₂, 5 to 15% EtOAc in hexanes) to affordcarbamate SI3 as a colorless oil (23.0 g, 87% yield). R_(f)=0.32 (20%EtOAc in hexanes); ¹H NMR (300 MHz, CDCl3) δ 5.88 (ddt, J=17.3, 10.4,5.7 Hz, 2H), 5.30 (dq, J=17.2, 1.6, 1.5 Hz, 2H), 5.23 (dq, J=10.4, 1.3,1.3 Hz, 2H), 4.61 (dt, J=5.6, 1.4 Hz, 4H), 4.55 (br s, 1H), 3.12 (q,J=6.7 Hz, 2H), 2.00-1.75 (m, 2H), 1.44 (m, 14H); ¹³C NMR (75 MHz, CDCl₃)δ 171.6, 155.8, 131.5, 118.4, 79.0, 65.7, 53.4, 40.4, 32.7, 28.3, 24.9,19.9; IR (Neat Film NaCl) 3403, 2977, 2939, 1734, 1517, 1366, 1250,1173, 985, 934 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₈H₂₉NO₆Na[M+Na]^(+:) 378.1887, found 378.1892.

Lactam SI4: To a cooled (0° C.) solution of carbamate SI3 (10.4 g, 30.6mmol, 1.00 equiv) in toluene (306 mL) was added trimethylaluminum (11.7mL, 61.1 mmol, 2.00 equiv) dropwise over 10 min. After 5 h the reactionwas allowed to warm to ambient temperature and stirred for an additional17 h. The reaction was cooled (0° C.), treated with brine (100 mL,CAUTION: Gas evolution and exotherm) in a dropwise manner over 30 min,and stirred until gas evolution ceased. The reaction mixture was thentreated with saturated aqueous sodium potassium tartrate (200 mL) andstirred for 4 h. The phases were separated and the aqueous phase wasextracted with EtOAc (5×150 mL). The combined organic phases were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting oil was purified by flash chromatography (5×16 cm SiO₂, 45 to65% EtOAc in hexanes) to afford lactam SI4 as a colorless oil (3.99 g,66% yield). R_(f)=0.41 (100% EtOAc); ¹H NMR (300 MHz, CDCl₃) δ 6.85 (s,1H), 6.00-5.75 (m, 1H), 5.30 (d, J=17.1 Hz, 1H), 5.20 (d, J=10.4 Hz,1H), 4.70-4.50 (m, 2H), 3.40-3.20 (m, 2H), 2.30-2.15 (m, 1H), 1.94-1.59(m, 3H), 1.48 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.1, 172.0, 131.7,118.1, 65.7, 50.1, 42.3, 33.0, 22.4, 19.3; IR (Neat Film NaCl) 3207,3083, 2942, 2873, 1737, 1668, 1254, 1194, 1132 cm⁻¹; HRMS (MM: ESI-APCI)m/z calc'd for C₁₀H₁₆NO₃ [M+H]⁺: 198.1125, found 198.1117.

As discussed in more detail below with respect to the specific Compounds1a through 1h, reactions were performed with Compound 1 (33.6 mmol),Pd₂(dba)₃ (5 mol %), and ligand (12.5 mol %) in solvent (1.0 mL) at 40°C. for 72 h (dba=dibenzylideneacetone). In all cases, completeconsumption of starting material and product formation was observed bythin layer chromatography on silica gel. Pd₂(pmdba)₃ (5 mol %) was usedfor Compounds 1a and 1b at 50° C.(pmdba=bis(4-methoxybenzylidene)acetone). Enantiomeric excess (ee) wasdetermined by chiral GC, SFC, or HPLC.

Compound 1h—R is Benzoyl

To a cooled (0° C.) solution of lactam SI4 (394 mg, 2.00 mmol, 1.00equiv), triethylamine (840 mL, 6.00 mmol, 3.00 equiv), and DMAP (25.0mg, 205 mmol, 0.102 equiv) in THF (8.00 mL) was added benzoyl chloride(470 mL, 4.00 mmol, 2.00 equiv) dropwise over 5 min. The reactionmixture was allowed to warm to ambient temperature and stirred for 14 h.The reaction mixture was then diluted with brine (10 mL) and EtOAc (10mL), and the phases were separated. The aqueous phase was extracted withEtOAc (3×15 mL), and the combined organic phases were washed with brine(2×30 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The resulting oil was purified by flash chromatography (3×25cm SiO₂, 15 to 25% Et₂O in hexanes) to afford benzoyl lactam 1h as anamorphous solid (550 mg, 91% yield). R_(f)=0.38 (25% EtOAc in hexanes);¹H NMR (500 MHz, CDCl₃) δ 7.78-7.63 (m, 2H), 7.52-7.42 (m, 1H),7.42-7.32 (m, 2H), 5.98 (ddt, J=17.2, 10.4, 5.9 Hz, 1H), 5.40 (dq,J=17.2, 1.4 Hz, 1H), 5.33 (dq, J=10.4, 1.2 Hz, 1H), 4.72 (dt, J=6.0, 1.3Hz, 2H), 3.93-3.82 (m, 1H), 3.83-3.73 (m, 1H), 2.56-2.43 (m, 1H),2.13-1.90 (m, 2H), 1.87-1.76 (m, 1H), 1.49 (s, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 174.9, 172.8, 172.4, 135.9, 131.6, 131.4, 128.0, 127.9, 119.5,66.5, 52.9, 46.8, 33.8, 22.5, 20.2; IR (Neat Film NaCl) 3063, 2941,2873, 1735, 1681, 1449, 1276, 1040, 942, 724 cm⁻¹; HRMS (MM: ESI-APCI)m/z calc'd for C₁₇H₂₀NO₄ [M+H]⁺: 302.1387, found 302.1388.

Compound 1a—R is Osyl

Compound 1a was made by the diallyl malonate method described above,except that the final reaction using lactam SI4 was replaced with thefollowing final reaction scheme.

Specifically, to a cooled (−78° C.) solution of LiHMDS (385 mg, 2.30mmol, 1.15 equiv) in THF (8.0 mL) was added lactam SI4 (394 mg, 2.00mmol, 1.00 equiv). The reaction mixture warmed to 0° C. and stirred for30 min, then cooled to −78° C. and treated with TsCl (572 mg, 3.00 mmol,1.50 equiv). After 5 min, the reaction mixture was allowed to warm toambient temperature for 30 min and treated with saturated aqueous NH₄Cl(10 mL). The phases were separated, and the aqueous phase was extractedwith EtOAc (3×20 mL). The combined organic phases were washed withsaturated aqueous NaHCO₃ (20 mL) and brine (20 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting oil waspurified by flash chromatography (3×30 cm SiO₂, 4:1:1 hexanes-EtOAc-DCM)to afford tosyl lactam 1a as a colorless oil (571 mg, 81% yield).R_(f)=0.58 (33% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.93-7.83(m, 2H), 7.35-7.27 (m, 2H), 5.68 (ddt, J=17.2, 10.5, 5.6 Hz, 1H), 5.17(dq, J=9.1, 1.4 Hz, 1H), 5.14 (q, J=1.4 Hz, 1H), 4.47 (qdt, J=13.2, 5.6,1.4 Hz, 2H), 3.98 (ddd, J=12.8, 6.9, 6.1 Hz, 1H), 3.90 (ddt, J=12.4,6.0, 0.8 Hz, 1H), 2.42 (s, 3H), 2.34-2.26 (m, 1H), 1.95 (tt, J=6.5, 5.5Hz, 2H), 1.71 (ddd, J=14.2, 8.1, 6.6 Hz, 1H), 1.41 (s, 3H); ¹³C NMR (126MHz, CDCl₃) δ 171.8, 169.9, 144.6, 135.7, 131.1, 129.2, 128.6, 118.7,66.1, 52.8, 46.4, 32.4, 22.3, 21.6, 20.4; IR (Neat Film NaCl) 2942,1740, 1691, 1353, 1284, 1167, 1090 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'dfor C₁₇H₂₁NO₅SNa [M+Na]+: 374.1033, found 374.1042.

Compound 1b—R is BOC (i.e., Tert-Butoxycarbonyl)

Compound 1b was prepared in a manner analogous to the tosyl lactam ofCompound 1a, but using lactam SI4 (394 mg, 2.00 mmol, 1.00 equiv) andBoc₂O (873 mg, 4.00 mmol, 2.00 equiv). Compound 1b (407 mg, 68% yield)was isolated as an amorphous solid by flash chromatography (SiO₂, 9 to11% Et₂O in hexanes). R_(f)=0.54 (25% EtOAc in hexanes); ¹H NMR (500MHz, CDCl₃) δ 5.95-5.81 (m, 1H), 5.33 (dq, J=17.2, 1.5 Hz, 1H), 5.22(dq, J=10.5, 1.5 Hz, 1H), 4.64 (m, 2H), 3.80-3.70 (m, 1H), 3.63-3.49 (m,1H), 2.43-2.33 (m, 1H), 1.98-1.77 (m, 2H), 1.75-1.66 (m, 1H), 1.52 (s,9H), 1.50 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.5, 170.9, 153.1,131.5, 118.4, 83.0, 65.9, 53.1, 46.0, 32.6, 28.0, 22.9, 20.1; IR (NeatFilm NaCl) 2981, 2939, 1772, 1719, 1457, 1393, 1294, 1282, 1254, 1152,988, 945, 852 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₅H₂₃NO₅Na[M+Na]⁺: 320.1468, found 320.1470.

Compound 1c—R is CBZ (i.e., Carboxybenzyl)

Compound 1c was prepared in a manner analogous to the tosyl lactam ofCompound 1a, but using lactam SI4 (394 mg, 2.00 mmol, 1.00 equiv) andCbzCl (682 mg, 4.00 mmol, 2.00 equiv). Compound 1c (325 mg, 49% yield)was isolated as a colorless oil by flash chromatography (SiO₂, 14 to 17%Et₂O in hexanes). R_(f)=0.34 (25% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.47-7.40 (m, 2H), 7.39-7.28 (m, 3H), 5.85 (ddt, J=17.1, 10.5,5.6 Hz, 1H), 5.30 (dq, J=10.5, 1.3 Hz, 1H), 5.29 (s, 2H), 5.19 (dq,J=10.5, 1.3 Hz, 1H), 4.69-4.54 (m, 2H), 3.86-3.79 (m, 1H), 3.71-3.60 (m,1H), 2.44-2.37 (m, 1H), 1.98-1.78 (m, 2H), 1.73 (ddd, J=14.0, 9.1, 5.1Hz, 1H), 1.52 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.3, 170.9, 154.4,135.4, 131.3, 128.5, 128.2, 128.0, 118.7, 68.6, 66.1, 53.3, 46.4, 32.5,22.8, 20.0; IR (Neat Film NaCl) 2943, 2876, 1776, 1721, 1456, 1378,1270, 1191, 1167, 1125, 1002, 941, 739, 698 cm⁻¹; HRMS (MM: ESI-APCI)m/z calc'd for C₁₈H₂₁NO₅Na [M+Na]⁺: 354.1312, found 354.1310.

Compound 1d—R is FMOC (i.e., Fluorenyl Methyloxycarbonyl)

Compound 1d was prepared in a manner analogous to the tosyl lactam ofCompound 1a, but using lactam SI4 (394 mg, 2.00 mmol, 1.00 equiv) andFmocCl (621 mg, 2.40 mmol, 1.20 equiv). Compound 1d (352 mg, 42% yield)was isolated as a colorless oil by flash chromatography (SiO₂, 2 to 12%Et₂O in hexanes). R_(f)=0.28 (25% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.77 (dt, J=7.6, 0.9 Hz, 2H), 7.73 (ddd, J=7.5, 5.0, 1.0 Hz,2H), 7.43-7.38 (m, 2H), 7.32 (tdd, J=7.4, 4.8, 1.2 Hz, 2H), 5.91 (ddt,J=17.2, 10.5, 5.6 Hz, 1H), 5.36 (dq, J=17.2, 1.5 Hz, 1H), 5.25 (dq,J=10.5, 1.3 Hz, 1H), 4.69 (ddt, J=5.6, 2.8, 1.4 Hz, 2H), 4.56-4.43 (m,2H), 4.33 (t, J=7.5 Hz, 1H), 3.86-3.79 (m, 1H), 3.73-3.61 (m, 1H), 2.44(dddd, J=13.8, 6.8, 5.0, 0.9 Hz, 1H), 2.00-1.83 (m, 2H), 1.78 (ddd,J=14.0, 9.1, 5.0 Hz, 1H), 1.59 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ172.3, 170.9, 154.5, 143.6, 141.2, 131.4, 127.8, 127.1, 125.4, 119.9,118.7, 69.3, 66.1, 53.4, 46.6, 46.4, 32.6, 22.9, 20.0; IR (Neat FilmNaCl) 2948, 2892, 1776, 1721, 1451, 1378, 1269, 1191, 997, 759, 742cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₂₅H₂₅NO₅Na [M+Na]⁺: 442.1625,found 442.1610.

Compound 1e—R is Acetyl

Compound 1e was prepared in a manner analogous to the benzoyl lactam ofCompound 1h, but using lactam SI4 (394 mg, 2.00 mmol, 1.00 equiv),acetic anhydride (940 mL, 10.0 mmol, 5.00 equiv), and triethylamine(2.80 mL, 20.0 mmol, 10.0 equiv). Compound 1e (347 mg, 72% yield) wasisolated as a colorless oil by flash chromatography (SiO₂, 12 to 25%Et₂O in hexanes). R_(f)=0.44 (25% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 5.88 (ddt, J=17.1, 10.4, 5.7 Hz, 1H), 5.31 (dq, J=17.2, 1.5 Hz,1H), 5.25 (dq, J=10.5, 1.2 Hz, 1H), 4.66-4.60 (m, 2H), 3.78 (ddd,J=13.1, 7.6, 5.3 Hz, 1H), 3.71-3.62 (m, 1H), 2.49 (s, 3H), 2.44-2.37 (m,1H), 1.93-1.77 (m, 2H), 1.78-1.70 (m, 1H), 1.52 (s, 3H); ¹³C NMR (126MHz, CDCl₃) δ 174.0, 173.5, 172.4, 131.3, 119.1, 66.2, 53.2, 44.0, 32.9,27.0, 22.7, 19.9; IR (Neat Film NaCl) 2985, 2942, 1739, 1699, 1457,1368, 1301, 1261, 1190, 1132, 1048, 990, 959, 936 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₁₂H₁₈NO₄ [M+H]⁺: 240.1230, found 240.1237.

Compound 1f—R is 4-OMe-Bz (i.e., 4-Methoxybenzoyl)

Compound 1f was prepared in a manner analogous to the benzoyl lactam ofCompound 1h, but using lactam SI4 (394 mg, 2.00 mmol, 1.00 equiv),4-methoxybenzoyl chloride (682 mg, 4.00 mmol, 2.00 equiv), andtriethylamine (840 mL, 6.00 mmol, 3.00 equiv). Compound 1f (425 mg, 64%yield) was isolated as a colorless oil by flash chromatography (SiO₂,CHCl₃-hexanes-Et₂O 6.5:5:1). R_(f)=0.76 (50% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.81-7.67 (m, 2H), 6.93-6.79 (m, 2H), 6.05-5.88 (m,1H), 5.39 (dq, J=17.2, 1.4 Hz, 1H), 5.31 (dq, J=10.4, 1.2 Hz, 1H), 4.71(dt, J=6.0, 1.3 Hz, 2H), 3.90-3.77 (m, 1H), 3.82 (s, 3H), 3.76-3.63 (m,1H), 2.48 (ddd, J=13.7, 5.7, 4.3 Hz, 1H), 2.06-1.89 (m, 2H), 1.80 (ddd,J=13.5, 10.0, 5.0 Hz, 1H), 1.49 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ174.3, 172.6 (2C), 162.7, 131.4, 130.7, 127.7, 119.3, 113.3, 66.3, 55.3,52.8, 46.9, 33.7, 22.5, 20.2; IR (Neat Film NaCl) 3080, 2941, 1732,1682, 1604, 1512, 1456, 1390, 1257, 1173, 1139, 1029, 939, 844, 770cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₈H₂₂NO₅ [M+H]⁺: 332.1492,found 332.1501.

Compound 1g—R is 4-F-Bz (i.e., 4-Fluorobenzoyl)

Compound 1g was prepared in a manner analogous to the benzoyl lactam ofCompound 1h, but using lactam SI4 (394 mg, 2.00 mmol, 1.00 equiv),4-fluorobenzoyl chloride (470 mL, 4.00 mmol, 2.00 equiv), andtriethylamine (840 mL, 6.00 mmol, 3.00 equiv). Compound 1g (557 mg, 87%yield) was isolated as an amorphous white solid by flash chromatography(SiO₂, 15 to 25% Et₂O in hexanes). R_(f)=0.37 (25% EtOAc in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 7.84-7.72 (m, 2H), 7.12-6.97 (m, 2H), 5.99 (ddt,J=17.2, 10.4, 5.9 Hz, 1H), 5.41 (dq, J=17.2, 1.4 Hz, 1H), 5.35 (dq,J=10.4, 1.2 Hz, 1H), 4.73 (dt, J=6.0, 1.3 Hz, 2H), 3.89-3.82 (m, 1H),3.81-3.75 (m, 1H), 2.57-2.42 (m, 1H), 2.09-1.91 (m, 2H), 1.89-1.75 (m,1H), 1.50 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.8, 172.9, 172.5, 164.8(d, J_(C-F)=252.5 Hz), 131.8 (d, J_(C-F)=3.3 Hz), 131.3, 130.7 (d,J_(C-F)=9.0 Hz), 119.5, 115.2 (d, J_(C-F)=22.0 Hz), 66.5, 52.9, 47.0,33.8, 22.4, 20.2; IR (Neat Film NaCl) 3079, 2943, 2874, 1734, 1684,1602, 1508, 1277, 1240, 1193, 1140, 939, 849, 770 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₁₇H₁₉NO₄F [M+H]⁺: 320.1293, found 320.1297.

General Procedure for Allylic Alkylation Screening Reactions

The substrates described above (i.e., Compounds 1a through 1h) were thensubjected to allylic alkylation reactions using different ligands andsolvents and the resulting compounds (i.e., Compounds 2a through 2h)were analyzed for enantiomeric excess. The general procedure for thesereactions is described here.

All reagents were dispensed as solutions using a Symyx Core Modulewithin a nitrogen-filled glovebox. Oven-dried half-dram vials werecharged with a solution of the palladium source (Pd₂dba₃ or Pd₂pmdba₃,1.68 μmol, 0.05 equiv) in THF (368 μL). The palladium solutions wereevaporated to dryness under reduced pressure using a Genevac centrifugalevaporator within the glovebox, and stirbars were added to the vials.The reaction vials were then charged with the desired reaction solvent(500 μL) and a solution of the PHOX ligand (4.20 μmol, 0.125 equiv) inthe reaction solvent (250 μL) and stirred at ambient gloveboxtemperature (˜28° C.). After 30 min, solutions of the lactam substrate(33.6 μmol, 1.0 equiv) in the reaction solvent (250 μL) were added. Thereaction vials were tightly capped and heated to the desiredtemperature. When complete consumption of the starting material wasobserved by colorimetric change (from light green to red-orange) andconfirmed by thin layer chromatography on SiO₂ (typically less than 72h), the reaction mixtures were removed from the glovebox, concentratedunder reduced pressure, resuspended in an appropriate solvent foranalysis (e.g., hexanes), filtered, and analyzed for enantiomericexcess. The methods for determining the enantiomeric excess are reportedin Table 4 below.

Results of the Screening of Various Reaction Parameters

The results of the enantiomeric excess analysis (by chiral HPLC (highperformance liquid chromatography)) of Compounds 2a through 2h (madefrom Compounds 1a through 1 h) over different N-protecting groups anddifferent solvents are reported in the below Table 2.

TABLE 2

THF MTBE Toluene Hex:Tol 2:1 R = Ts^(a)  4.1 25.9  6.5 31.4 35.2 57.237.2 44.2 R = Boc^(a) 57.3 74.5 73.6 76.7 70.3 72.1 73.0 71.0 R = Cbz36.3 75.2 75.1 71.5 79.9 83.5 87.3 83.2 R = Fmoc 45.7 64.9 38.3 44.978.9 84.6 87.1 84.6 R = Ac 20.0 64.1 61.6 83.2 75.1 90.6^(b) 90.2^(b)90.9^(b) R = 4-MeO-Bz 59.5 90.7 87.4 96.8 97.1 98.3 99.0 98.5 R = 4-F-Bz42.3 85.8 83.2 96.4 95.3 99.0 99.3 99.4 R = Bz 52.2 88.3 85.8 96.4 96.299.2 99.0 98.8 ^(a)Reactions for these substrates run at 50° C.^(b)Reaction performed at 60° C.Characterization Data for New Product Compounds 2a through 2h

The new compounds 2a through 2h were formed using the reactions below,and characterized. The results of the characterizations are reported inTable 3 below.

Tosyl Lactam 2a

The reaction was performed in MTBE at 40° C. Tosyl lactam 2a wasisolated by flash chromatography (SiO₂, 3 to 15% Et₂O in hexanes) as alight yellow solid. 90.0% yield. R_(f)=0.29 (35% Et₂O in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 7.89-7.84 (m, 2H), 7.33-7.27 (m, 2H), 5.41 (dddd,J=16.9, 10.2, 8.1, 6.7 Hz, 1H), 4.99-4.86 (m, 2H), 3.99 (dddd, J=11.9,5.9, 4.9, 1.3 Hz, 1H), 3.82-3.71 (m, 1H), 2.42 (s, 3H), 2.41-2.34 (m,1H), 2.07 (ddt, J=13.6, 8.1, 1.0 Hz, 1H), 1.98-1.83 (m, 2H), 1.83-1.75(m, 1H), 1.55-1.48 (m, 1H), 1.12 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ175.7, 144.4, 136.2, 132.9, 129.2, 128.5, 118.9, 47.6, 44.2, 44.0, 32.1,25.5, 21.6, 20.1; IR (Neat Film NaCl) 3074, 2938, 1689, 1597, 1454,1351, 1283, 1171, 1103, 1089, 1039, 921, 814, 748 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₁₆H₂₁NO₃SNa [M+Na]⁺: 330.1134, found 330.1141;[α]D²⁵−69.2° (c 1.16, CHCl₃, 75% ee).

Boc Lactam 2b

The reaction was performed in toluene at 40° C. Boc lactam 2b wasisolated by flash chromatography (SiO₂, 8 to 9% Et₂O in hexanes) as acolorless oil. 87.1% yield. R_(f)=0.57 (35% Et₂O in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 5.74 (dddd, J=17.1, 10.4, 7.8, 7.0 Hz, 1H), 5.14-5.02(m, 2H), 3.71-3.61 (m, 1H), 3.58-3.48 (m, 1H), 2.48 (dd, J=13.6, 7.0 Hz,1H), 2.26 (dd, J=13.6, 7.9 Hz, 1H), 1.87-1.76 (m, 3H), 1.61-1.52 (m,1H), 1.50 (s, 9H), 1.22 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.1,153.7, 133.7, 118.5, 82.5, 47.4, 44.5, 44.2, 33.0, 28.0, 25.4, 19.7; IR(Neat Film NaCl) 3076, 2978, 2936, 1768, 1715, 1457, 1392, 1368, 1298,1280, 1252, 1149, 999, 917, 854 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₁₄H₂₃NO₃Na [M+Na]⁺: 276.1570, found 276.1574; [α]D²⁵ −73.6° (c 1.025,CHCl₃, 81% ee).

Cbz Lactam 2c

The reaction was performed in toluene at 40° C. Cbz lactam 2c wasisolated by flash chromatography (SiO₂, 8 to 10% Et₂O in hexanes) as acolorless oil. 84.6% yield. R_(f)=0.49 (25% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.44-7.40 (m, 2H), 7.36 (ddd, J=7.9, 7.0, 1.0 Hz,2H), 7.33-7.29 (m, 1H), 5.74 (dddd, J=16.6, 10.5, 7.8, 6.9 Hz, 1H), 5.26(s, 2H), 5.13-5.02 (m, 2H), 3.80-3.72 (m, 1H), 3.67-3.58 (m, 1H), 2.51(dd, J=13.6, 7.0 Hz, 1H), 2.26 (dd, J=13.6, 7.9 Hz, 1H), 1.90-1.77 (m,3H), 1.62-1.53 (m, 1H), 1.25 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.0,154.8, 135.6, 133.4, 128.5, 128.2, 128.0, 118.8, 68.3, 47.8, 44.8, 44.2,32.8, 25.5, 19.6; IR (Neat Film NaCl) 2940, 1772, 1712, 1456, 1377,1296, 1270, 1218, 1161, 1001, 918 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'dfor C₁₇H₂₀NO₃Na [M+Na]⁺: 310.1414, found 310.1414; [α]D²⁵ −65.8° (c1.48, CHCl₃, 86% ee).

Fmoc Lactam 2d

The reaction was performed in toluene at 40° C. Fmoc lactam 2d wasisolated by flash chromatography (SiO₂, 6 to 8% Et₂O in hexanes) as acolorless oil. 82.4% yield. R_(f)=0.45 (25% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.77 (dt, J=7.6, 1.0 Hz, 2H), 7.71 (ddd, J=7.5, 3.6,1.0 Hz, 2H), 7.41 (tt, J=7.5, 0.9 Hz, 2H), 7.33 (ddt, J=7.5, 2.0, 1.2Hz, 2H), 5.80 (dddd, J=17.9, 8.7, 7.9, 6.9 Hz, 1H), 5.18-5.10 (m, 2H),4.53-4.42 (m, 2H), 4.33 (t, J=7.4 Hz, 1H), 3.80-3.71 (m, 1H), 3.65-3.57(m, 1H), 2.58 (dd, J=13.6, 7.0 Hz, 1H), 2.32 (ddt, J=13.6, 7.8, 1.1 Hz,1H), 1.93-1.79 (m, 3H), 1.64-1.57 (m, 1H), 1.31 (s, 3H); ¹³C NMR (126MHz, CDCl₃) δ 177.0, 154.9, 143.7, 141.2, 133.5, 127.7, 127.1, 125.4,119.9, 118.8, 68.9, 47.7, 46.7, 44.8, 44.2, 32.8, 25.5, 19.6; IR (NeatFilm NaCl) 3067, 2945, 1770, 1712, 1478, 1451, 1377, 1297, 1269, 1161,1000, 759, 740 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₂₄H₂₆NO₃[M+H]⁺: 376.1907, found 376.1914; [α]D²⁵ −38.5° (c 2.17, CHCl₃, 89% ee).

Acetyl Lactam 2e

The reaction was performed in toluene at 40° C. Acetyl lactam 2e wasisolated by flash chromatography (SiO₂, 8 to 10% Et₂O in hexanes) as acolorless oil. 47.2% yield. R_(f)=0.38 (25% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 5.73 (dddd, J=16.6, 10.4, 7.8, 7.0 Hz, 1H), 5.14-5.04(m, 2H), 3.82-3.72 (m, 1H), 3.60-3.49 (m, 1H), 2.50 (ddt, J=13.6, 7.0,1.2 Hz, 1H), 2.44 (s, 3H), 2.25 (ddt, J=13.6, 7.7, 1.1 Hz, 1H),1.91-1.71 (m, 3H), 1.64-1.52 (m, 1H), 1.25 (s, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 179.3, 174.4, 133.3, 118.9, 45.4, 44.8, 44.4, 32.8, 27.2, 25.7,19.4; IR (Neat Film NaCl) 2941, 1694, 1387, 1367, 1293, 1248, 1177,1114, 1046, 920 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₁H₁₈NO₂[M+H]⁺: 196.1332, found 196.1329; [α]D25 −100.9° (c 0.99, CHCl₃, 91%ee).

4-Methoxybenzoyl Lactam 2f

The reaction was performed in toluene at 40° C. 4-Methoxybenzoyl lactam2f was isolated by flash chromatography (SiO₂, 15% EtOAc in hexanes) asa colorless oil. 92.7% yield. R_(f)=0.36 (25% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.60-7.48 (m, 2H), 6.92-6.82 (m, 2H), 5.76 (dddd,J=17.2, 10.3, 7.7, 7.0 Hz, 1H), 5.19-5.03 (m, 2H), 3.83 (s, 3H), 3.80(ddd, J=12.1, 5.3, 1.4 Hz, 1H), 3.73-3.64 (m, 1H), 2.57 (ddt, J=13.6,7.1, 1.2 Hz, 1H), 2.29 (ddt, J=13.7, 7.6, 1.1 Hz, 1H), 2.05-1.91 (m,3H), 1.72-1.63 (m, 1H), 1.32 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 179.0,174.9, 162.4, 133.4, 130.1, 128.4, 118.9, 113.5, 55.4, 47.3, 43.9, 43.4,33.3, 25.3, 19.6; IR (Neat Film NaCl) 2937, 1675, 1604, 1511, 1254,1164, 1029, 922, 840, 770 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₁₇H₂₂NO₃ [M+H]⁺: 288.1594, found 288.1595; [α]D²⁵ −94.2° (c 1.00,CHCl₃, 99% ee).

4-Fluorobenzoyl Lactam 2g

The reaction was performed in toluene at 40° C. 4-Fluorobenzoyl lactam2g was isolated by flash chromatography (SiO₂, 9% Et₂O in hexanes) as acolorless oil. 89.4% yield. R_(f)=0.41 (17% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.59-7.47 (m, 2H), 7.12-6.99 (m, 2H), 5.74 (ddt,J=17.0, 10.4, 7.3 Hz, 1H), 5.18-5.05 (m, 2H), 3.89-3.77 (m, 1H),3.77-3.63 (m, 1H), 2.55 (dd, J=13.7, 7.0 Hz, 1H), 2.28 (dd, J=13.7, 7.6Hz, 1H), 2.07-1.88 (m, 3H), 1.76-1.62 (m, 1H), 1.31 (s, 3H); ¹³C NMR(126 MHz, CDCl₃) δ 179.1, 174.2, 164.6 (d, J_(C-F)=252.4 Hz), 133.2,132.5 (d, J_(C-F)=3.4 Hz), 123.0 (d, J_(C-F)=8.9 Hz), 119.1, 115.3 (d,J_(C-F)=22.1 Hz), 47.3, 44.0, 43.3, 33.3, 25.2, 19.5; IR (Neat FilmNaCl) 3076, 2940, 1679, 1602, 1507, 1384, 1280, 1145, 922, 844, 769cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₆H₁₉NO₂F [M+H]⁺: 276.1394,found 276.1392; [α]D²⁵ −85.5° (c 1.02, CHCl₃, 99% ee).

Benzoyl Lactam 2H

The reaction was performed in toluene at 40° C. Benzoyl lactam 2H wasisolated by flash chromatography (SiO₂, 5 to 9% Et₂O in pentane) as acolorless oil. 84.7% yield. R_(f)=0.55 (25% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.54-7.50 (m, 2H), 7.49-7.43 (m, 1H), 7.40-7.35 (m,2H), 5.75 (dddd, J=17.1, 10.2, 7.7, 7.0 Hz, 1H), 5.19-5.03 (m, 2H),3.92-3.78 (m, 1H), 3.72 (ddt, J=12.6, 6.4, 6.0, 1.2 Hz, 1H), 2.55 (ddt,J=13.7, 7.0, 1.2 Hz, 1H), 2.29 (ddt, J=13.7, 7.7, 1.1 Hz, 1H), 2.07-1.87(m, 3H), 1.75-1.60 (m, 1H), 1.31 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ179.0, 175.3, 136.5, 133.3, 131.3, 128.1, 127.4, 118.9, 47.1, 44.0,43.3, 33.3, 25.1, 19.5; IR (Neat Film NaCl) 3074, 2939, 2870, 1683,1478, 1449, 1386, 1282, 1151, 919, 726, 695 cm⁻¹; HRMS (MM: ESI-APCI)m/z calc'd for C₁₆H₂₀NO₂ [M+H]⁺: 258.1489, found 258.1491; [α]D²⁵ −91.2°(c 1.07, CHCl₃, 99% ee).

TABLE 3

entry temperature (° C.) concentration (M) time (h) % ee 1 40 0.033 4399.2 2 45 0.033 22 98.9 3 50 0.033 12 98.7 4 55 0.033  6 98.2 5 40 0.1043 98.9 6 40 0.20 43 97.4

Preparation of Substrates for the Creation of N-acyl Lactam Derivatives

The N-acyl lactam derivatives discussed above and depicted in Table 1,above, were prepared using substrates prepared according to an Acylationand Alkylation Method. A representative reaction scheme for theacylation and alkylation method is depicted in the below

Acylation and Alkylation Method Reaction Scheme.

In the above Acylation and Alkylation Method Reaction Scheme, acyllactam SI6 and benzoyl lactam SI6 were prepared according to thefollowing procedures. Also, although the final reaction depicted in theAcylation and Alkylation Method Reaction Scheme describes the reactionused to form benzoyl lactam SI7, analogous reactions can be used to formsubstrates for certain of the remaining compounds depicted in Table 1above. as also described below. Additionally, some of the substrateswere formed using the diallyl malonate method described above, asdescribed below.

Acyl Lactam S16: To a cooled (0° C.) solution of diisopropylamine (3.33mL, 23.6 mmol, 1.20 equiv) in THF (131 mL) was added a solution ofn-BuLi (8.84 mL, 21.7 mmol, 2.45 M in hexanes, 1.10 equiv) dropwise over10 min. After 30 min at 0° C., the reaction mixture was cooled to −78 °C. A solution of benzoyl lactam SI5⁷ (4.00 g, 19.7 mmol, 1.00 equiv) inTHF (25 mL) was added dropwise over 10 min. After an additional 2 h, thereaction mixture was warmed to −30° C. for 1 h, cooled to −78° C., andtreated with allyl cyanoformate (2.41 g, 21.7 mmol, 1.10 equiv). Thereaction mixture was maintained at −78° C. for 2 h, allowed to warm toambient temperature with stirring over 14 h, and diluted withhalf-saturated brine (100 mL) and EtOAc (100 mL). The phases wereseparated, and the aqueous phase was extracted with EtOAc (4×100 mL).The combined organic phases were washed with brine (2×100 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting oil was purified by flash chromatography (5×30 cm SiO₂, 15 to30% EtOAc in hexanes) to afford acyl lactam SI6 as a colorless oil (4.18g, 74% yield). R_(f)=0.43 (35% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.75-7.62 (m, 2H), 7.52-7.43 (m, 1H), 7.42-7.33 (m, 2H), 5.95(ddt, J=17.2, 10.4, 5.9 Hz, 1H), 5.37 (dq, J=17.2, 1.5 Hz, 1H), 5.29(dq, J=10.4, 1.2 Hz, 1H), 4.75-4.60 (m, 2H), 3.95-3.72 (m, 2H), 3.59 (t,J=6.4 Hz, 1H), 2.42-2.25 (m, 1H), 2.26-2.14 (m, 1H), 2.12-2.03 (m, 1H),2.01-1.89 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.5, 169.5, 169.2,135.4, 131.9, 131.4, 128.2, 128.1, 119.3, 66.4, 51.1, 46.3, 25.5, 20.7;IR (Neat Film NaCl) 3063, 2952, 1738, 1682, 1449, 1284, 1152, 730, 700cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₆H₁₈NO₄ [M+H]⁺: 288.1230,found 288.1221.

Benzoyl Lactam SI7: To a mixture of acyl lactam SI6 (750 mg, 2.61 mmol,1.00 equiv) K₂CO₃ (1.80 g, 13.1 mmol, 5.00 equiv) in acetone (10.5 mL)was added acrylonitrile (344 μL, 5.22 mmol, 2.00 equiv). The reactionmixture was heated (55° C.) for 6 h, then cooled to ambient temperatureand filtered. The retentate was washed with acetone (2×10 mL). Thecombined organic phases were concentrated under reduced pressure. Theresulting oil was purified by flash chromatography (3×30 cm SiO₂, 5 to30% EtOAc in hexanes) to afford benzoyl lactam S17 as a colorless oil(654 mg, 74% yield). R_(f)=0.23 (20% EtOAc in hexanes developed twice);¹H NMR (500 MHz, CDCl₃) δ 7.77-7.66 (m, 2H), 7.56-7.45 (m, 1H),7.43-7.34 (m, 2H), 6.00 (ddt, J=17.2, 10.3, 6.2 Hz, 1H), 5.44 (dq,J=17.1, 1.3 Hz, 1H), 5.38 (dq, J=10.3, 1.1 Hz, 1H), 4.77 (ddt, J=6.1,3.1, 1.2 Hz, 2H), 3.85 (ddd, J=13.0, 9.6, 5.4 Hz, 1H), 3.76 (ddt,J=13.0, 4.9, 1.4 Hz, 1H), 2.61 (ddd, J=17.0, 8.4, 6.9 Hz, 1H), 2.53-2.35(m, 2H), 2.22 (ddd, J=8.8, 6.7, 1.6 Hz, 2H), 2.12-1.95 (m, 2H), 1.89(ddd, J=13.6, 10.1, 5.3 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.6,171.2, 170.6, 135.4, 132.0, 130.8, 128.2, 128.1, 120.5, 119.1, 67.0,55.4, 46.4, 31.7, 31.5, 20.0, 13.5; IR (Neat Film NaCl) 3067, 2952,2248, 1733, 1683, 1449, 1271, 1196, 1175, 1152, 943, 725 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₁₉H₂₁N₂O₄ [M+H]⁺: 341.1496, found 341.1492.

Benzoyl Lactam SI8

Benzoyl lactam SI8 was prepared by the diallyl malonate method usingdiallyl 2-ethylmalonate as a starting material. Benzoyl lactam SI8 wasisolated by flash chromatography (SiO₂, 15 to 25% Et₂O in hexanes) as acolorless oil. R_(f)=0.38 (35% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃)δ 7.72-7.67 (m, 2H), 7.51-7.43 (m, 1H), 7.37 (dd, J=8.3, 7.1 Hz, 2H),5.99 (ddt, J=17.3, 10.4, 5.9 Hz, 1H), 5.40 (dq, J=17.2, 1.4 Hz, 1H),5.33 (dq, J=10.4, 1.2 Hz, 1H), 4.73 (dt, J=6.0, 1.3 Hz, 2H), 3.93-3.63(m, 2H), 2.43 (ddt, J=13.7, 4.4, 1.4 Hz, 1H), 2.17-1.65 (m, 5H), 0.91(t, J=7.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.0, 172.0, 171.8,135.9, 131.6, 131.4, 128.0 (2C), 119.5, 66.4, 56.9, 46.4, 29.8, 28.6,20.3, 9.0; IR (Neat Film NaCl) 3062, 2943, 2882, 1732, 1678, 1449, 1385,1268, 1188, 1137, 980, 937, 723, 693, 660 cm⁻¹; HRMS (MM: ESI-APCI) m/zcalc'd for C₁₈H₂₂NO₄ [M+H]⁺: 316.1543, found 316.1545.

Benzoyl Lactam SI9

Benzoyl lactam SI9 was prepared by the diallyl malonate method usingdiallyl 2-benzylmalonate as a starting material. Benzoyl lactam S19 wasisolated by flash chromatography (SiO₂, 15 to 35% Et₂O in hexanes) as acolorless oil. R_(f)=0.32 (35% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃)δ 7.72 (dt, J=8.2, 0.9 Hz, 2H), 7.56-7.45 (m, 1H), 7.45-7.35 (m, 2H),7.30-7.18 (m, 3H), 7.17-7.10 (m, 2H), 6.00 (ddt, J=17.2, 10.4, 6.0 Hz,1H), 5.43 (dq, J=17.2, 1.4 Hz, 1H), 5.36 (dq, J=10.4, 1.1 Hz, 1H), 4.75(dq, J=6.1, 1.1 Hz, 2H), 3.70 (dddd, J=12.9, 5.0, 4.3, 1.7 Hz, 1H), 3.59(ddd, J=12.9, 10.5, 4.6 Hz, 1H), 3.47 (d, J=13.7 Hz, 1H), 3.14 (d,J=13.7 Hz, 1H), 2.36 (ddt, J=13.7, 4.3, 1.7 Hz, 1H), 2.07-1.92 (m, 1H),1.91-1.75 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 175.0, 171.5, 171.3,135.9, 135.7, 131.8, 131.2, 130.9, 128.3, 128.2, 128.0, 127.0, 119.8,66.7, 57.8, 46.2, 40.6, 29.8, 20.1; IR (Neat Film NaCl) 3062, 3029,2941, 2890, 1731, 1701, 1682, 1449, 1273, 1190, 1147, 934, 723, 702, 661cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₂₃H₂₄NO₄ [M+H]⁺: 378.1700,found 378.1706.

Benzoyl Lactam SI10

Benzoyl lactam SI10 was prepared by the acylation and alkylation methodusing methyl acrylate as an alkylating reagent. Benzoyl lactam SI10 wasisolated by flash chromatography (SiO₂, 40 to 50% Et₂O in hexanes) as acolorless oil. R_(f)=0.28 (35% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃)δ 7.78-7.66 (m, 2H), 7.52-7.42 (m, 1H), 7.38 (t, J=7.7 Hz, 2H),6.04-5.93 (m, 1H), 5.41 (dq, J=17.1, 1.1 Hz, 1H), 5.35 (dt, J=10.4, 1.0Hz, 1H), 4.79-4.68 (m, 2H), 3.88-3.79 (m, 1H), 3.79-3.72 (m, 1H), 3.63(s, 3H), 2.56-2.41 (m, 2H), 2.40-2.28 (m, 1H), 2.27-2.18 (m, 2H),2.08-1.92 (m, 2H), 1.85 (ddd, J=15.2, 9.8, 5.7 Hz, 1H); ¹³C NMR (126MHz, CDCl₃) δ 174.8, 173.1, 171.6, 171.3, 135.7, 131.7, 131.1, 128.0(2C), 119.9, 66.6, 55.8, 51.7, 46.4, 31.0, 30.5, 29.7, 20.1; IR (NeatFilm NaCl) 2952, 1735, 1685, 1449, 1273, 1194, 1174, 726 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₂₀H₂₄NO₆ [M+H]⁺: 374.1598, found 374.1592.

Benzoyl Lactam SI11

Benzoyl lactam SI11 was prepared the acylation and alkylation method,above, using (2-bromoethoxy)-tert-butyldimethylsilane as an alkylatingreagent. Benzoyl lactam SI11 was isolated by flash chromatography (SiO₂,10 to 40% Et₂O in hexanes) as a colorless oil. R_(f)=0.18 (10% Et₂O inhexanes); ^(1H) NMR (500 MHz, CDCl₃) δ 7.74-7.62 (m, 2H), 7.52-7.42 (m,1H), 7.40-7.30 (m, 2H), 5.98 (ddt, J=17.1, 10.4, 6.0 Hz, 1H), 5.40 (dq,J=17.2, 1.4 Hz, 1H), 5.33 (dq, J=10.4, 1.2 Hz, 1H), 4.72 (dt, J=6.0, 1.3Hz, 2H), 3.80 (ddt, J=6.4, 4.8, 2.4 Hz, 2H), 3.72 (td, J=6.4, 0.8 Hz,2H), 2.55-2.31 (m, 1H), 2.23 (dt, J=14.1, 6.6 Hz, 1H), 2.16-2.03 (m,2H), 2.02-1.92 (m, 2H), 0.86 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); ¹³CNMR (126 MHz, CDCl₃) δ 175.0, 171.7 (2C), 136.0, 131.6, 131.4, 128.0(2C), 119.6, 66.5, 59.5, 55.3, 46.4, 37.8, 30.6, 25.9, 20.3, 18.2,−5.45, −5.47; IR (Neat Film NaCl) 2954, 2929, 2884, 2856, 1735, 1703,1683, 1276, 1255, 1143, 1092, 836 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'dfor C₂₄H₃₆NO₅Si [M+H]⁺: 446.2357, found 446.2361.

Benzoyl Lactam SI12

Benzoyl lactam SI12 was prepared by the diallyl malonate usingdimethallyl malonate as a starting material. Benzoyl lactam SI12 wasisolated by flash chromatography (SiO₂, 14 to 20% Et₂O in hexanes) as anamorphous white solid. R_(f)=0.47 (25% EtOAc in hexanes); ¹H NMR δ7.73-7.68 (m, 2H), 7.49-7.44 (m, 1H), 7.37 (ddd, J=8.1, 6.7, 1.2 Hz,2H), 5.05 (s, 1H), 5.01 (s, 1H), 4.65 (dd, J=17.5, 10.0 Hz, 2H), 3.87(ddd, J=12.9, 8.8, 5.6 Hz, 1H), 3.80 (ddt, J=12.9, 5.2, 1.4 Hz, 1H),2.55-2.46 (m, 1H), 2.08-1.95 (m, 2H), 1.86-1.79 (m, 1H), 1.79 (s, 3H),1.50 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.9, 172.8, 172.5, 139.3,135.9, 131.6, 128.0 (2C), 114.2, 69.1, 53.0, 46.8, 33.8, 22.5, 20.3,19.6; IR (Neat Film NaCl) 2941, 2873, 1735, 1682, 1449, 1276, 1192,1140, 940, 724, 694, 659 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₁₈H₂₁NO₄Na [M+Na]⁺: 338.1363, found 338.1373.

Benzoyl Lactam SI13

Benzoyl lactam SI13 was prepared by the diallyl malonate method usingdi-2-chloroallyl malonate as a starting material. Benzoyl lactam SI13was isolated by flash chromatography (SiO₂, 14 to 20% Et₂O in hexanes)as a colorless oil. R_(f)=0.47 (25% EtOAc in hexanes); ^(1H) NMR (500MHz, CDCl₃) δ 7.76-7.64 (m, 2H), 7.56-7.41 (m, 1H), 7.43-7.31 (m, 2H),5.54 (dt, J=2.0, 1.1 Hz, 1H), 5.48 (d, J=1.8 Hz, 1H), 4.80 (qd, J=13.4,1.0 Hz, 2H), 3.89 (ddd, J=12.9, 8.9, 5.1 Hz, 1H), 3.80 (ddt, J=13.0,5.3, 1.3 Hz, 1H), 2.52 (dddd, J=13.8, 5.6, 4.1, 1.3 Hz, 1H), 2.11-1.94(m, 2H), 1.85 (ddd, J=13.8, 10.2, 4.5 Hz, 1H), 1.53 (s, 3H); ¹³C NMR(126 MHz, CDCl₃) δ 174.9, 172.5, 172.1, 135.8, 135.3, 131.7, 128.1,128.0, 116.4, 67.1, 52.9, 46.7, 33.7, 22.5, 20.1; IR (Neat Film NaCl)2943, 2873, 1740, 1682, 1449, 1390, 1276, 1192, 1124, 1061, 943, 724,695 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₇H₁₈NO₄ClNa [M+Na]⁺:358.0817 found 358.0819.

Benzoyl Lactam SI14

Benzoyl lactam SI14 was prepared by the acylation and alkylation methodusing N-benzoyl pyrrolidinone as a starting material and methyl iodideas an alkylating reagent. See Amat, et al., “Enantioselective Synthesisof 3,3-Disubstituted Piperidine Derivatives by Enolate Dialkylation ofPhenylglycinol-derived Oxazolopiperidone Lactams,”J. Org. Chem. 72,4431-4439 (2007), the entire content of which is incorporated herein byreference. Benzoyl lactam SI14 was isolated by flash chromatography(SiO₂, 5 to 20% EtOAc in hexanes) as a colorless oil. R_(f)=0.45 (35%EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.64-7.55 (m, 2H),7.56-7.46 (m, 1H), 7.45-7.35 (m, 2H), 5.92 (ddt, J=17.2, 10.5, 5.7 Hz,1H), 5.34 (dq, J=17.2, 1.5 Hz, 1H), 5.28 (dq, J=10.4, 1.2 Hz, 1H), 4.67(dt, J=5.7, 1.4 Hz, 2H), 4.02 (ddd, J=11.3, 8.4, 4.6 Hz, 1H), 3.95 (dt,J=11.3, 7.7 Hz, 1H), 2.64 (ddd, J=13.2, 7.7, 4.5 Hz, 1H), 2.06 (ddd,J=13.2, 8.5, 7.6 Hz, 1H), 1.51 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ173.0, 170.9, 170.5, 133.9, 132.0, 131.2, 128.8, 127.8, 119.0, 66.4,53.8, 43.3, 30.5, 20.0; IR (Neat Film NaCl) 2985, 2938, 1750, 1738,1733, 1683, 1449, 1362, 1307, 1247, 1196, 1136, 972, 937, 860, 730, 699,656 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₆H₁₈NO₄ [M+H]⁺: 288.1230,found 288.1228.

Benzoyl Lactam SI15

Benzoyl lactam SI15 was prepared by the acylation and alkylation methodusing N-benzoyl pyrrolidinone as a starting material and4-(trifluoromethyl)benzyl bromide as an alkylating reagent. See Enders,et al., “Asymmetric Electrophilic Substitutions at the α-Position of γ-and δ-Lactams,” Eur. J. Org. Chem. 4463-4477 (2011), the entire contentof which is incorporated herein by reference. Benzoyl lactam SI15 wasisolated by flash chromatography (SiO₂, 10 to 20% EtOAc in hexanes) as acolorless oil. R_(f)=0.28 (20% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.58 (d, J=7.9 Hz, 2H), 7.56-7.49 (m, 3H), 7.44-7.38 (m, 2H),7.35 (d, J=7.9 Hz, 2H), 5.92 (ddt, J=17.3, 10.4, 5.8 Hz, 1H), 5.36 (dq,J=17.2, 1.4 Hz, 1H), 5.30 (dq, J=10.5, 1.2 Hz, 1H), 4.70 (dq, J=5.8, 1.2Hz, 2H), 3.84 (ddd, J=11.2, 8.6, 7.6 Hz, 1H), 3.66 (ddd, J=11.2, 8.8,3.2 Hz, 1H), 3.39 (d, J=14.0 Hz, 1H), 3.31 (d, J=13.9 Hz, 1H), 2.51(ddd, J=13.3, 7.6, 3.3 Hz, 1H), 2.15 (dt, J=13.3, 8.7 Hz, 1H); ¹³C NMR(126 MHz, CDCl₃) δ 171.3, 170.2, 169.8, 139.7 (d, J_(C-F)=1.5 Hz),133.7, 132.3, 131.0, 130.9, 129.8 (q, J_(C-F)=32.5 Hz), 128.9, 127.9,125.5 (q, J_(C-F)=3.8 Hz), 124.0 (q, J_(C-F)=272.0 Hz), 119.5, 66.8,59.0, 43.6, 38.4, 26.2; IR (Neat Film NaCl) 3062, 2938, 2913, 1751,1733, 1683, 1449, 1366, 1326, 1294, 1250, 1193, 1165, 1116, 1068, 861,728 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₂₃H₂₁NO₄F₃ [M+H]⁺:432.1417, found 432.1425.

Benzoyl Lactam SI16

Benzoyl Lactam SI16 was prepared by the acylation and alkylation methodusing N-benzoyl pyrrolidinone as a starting material and usingSelectfluor as a fluorinating agent. See Enders, et al., “AsymmetricElectrophilic Substitutions at the α-Position of γ- and b δ-Lactams,”Eur. J. Org. Chem. 4463-4477 (2011); Trost, et al., “Asymmetricsyntheses of oxindole and indole spirocyclic alkaloid natural products,”Synthesis 3003-3025 (2009), the entire contents of both which isincorporated herein by reference. Benzoyl lactam SI16 was isolated byflash chromatography (SiO₂, 10 to 20% EtOAc in hexanes) as a colorlessoil. R_(f)=0.28 (20% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.66-7.59 (m, 2H), 7.59-7.50 (m, 1H), 7.46-7.37 (m, 2H), 5.92 (ddt,J=17.2, 10.4, 5.8 Hz, 1H), 5.38 (dq, J=17.2, 1.4 Hz, 1H), 5.32 (dq,J=10.4, 1.1 Hz, 1H), 4.77 (dt, J=5.9, 1.3 Hz, 2H), 4.15 (ddd, J=11.2,8.8, 4.2 Hz, 1H), 4.01 (dddd, J=11.3, 7.7, 7.0, 2.0 Hz, 1H), 2.80 (dddd,J=14.1, 13.4, 7.8, 4.2 Hz, 1H), 2.53 (dddd, J=23.0, 14.2, 8.8, 7.1 Hz,1H); ¹³C NMR (126 MHz, CDCl₃) δ 169.8, 166.0 (d, J=10.2 Hz), 165.8 (d,J=5.5 Hz), 132.9, 132.7, 130.4, 129.0, 128.0, 120.0, 94.4 (d, J=203.6Hz), 67.2, 42.3 (d, J=2.9 Hz), 29.0 (d, J=21.7 Hz); IR (Neat Film NaCl)3062, 2987, 2917, 1773, 1690, 1449, 1373, 1290, 1257, 1198, 1161, 1118,1076, 983, 942, 859, 796, 731 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₁₆H₁₉NO₅F [M+MeOH+H]⁺: 324.1242, found 324.1244.

4-Methoxybenzoyl Lactam SI17

4-Methoxy benzoyl lactam SI17 was prepared by a combination of knownmethods and the diallyl malonate method. See Badillo, et al.,“Enantioselective synthesis of oxindoles and spirooxindoles withapplications in drug discovery,” Curr. Opin. Drug Disc. Dev. 13, 758-776(2010), the entire content of which is incorporated herein by reference.Benzoyl lactam SI17 was isolated by flash chromatography (SiO₂, 15 to25% Et₂O in hexanes) as a colorless oil. R_(f)=0.38 (35% Et₂O inhexanes); ^(1H) NMR (500 MHz, CDCl₃) δ 7.79-7.68 (m, 2H), 6.94-6.80 (m,2H), 5.99 (ddt, J=17.1, 10.4, 6.1 Hz, 1H), 5.43 (dq, J=17.2, 1.4 Hz,1H), 5.34 (dq, J=10.4, 1.1 Hz, 1H), 4.76 (dt, J=6.1, 1.2 Hz, 2H),4.28-4.16 (m, 1H), 3.84 (s, 3H), 3.15 (ddd, J=15.6, 11.1, 1.2 Hz, 1H),2.28-2.17 (m, 1H), 2.01-1.87 (m, 2H), 1.87-1.76 (m, 1H), 1.63 (ddd,J=14.8, 11.8, 3.7 Hz, 2H), 1.48 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ175.1, 174.6, 172.8, 162.6, 131.3, 130.7, 128.2, 119.9, 113.5, 66.2,55.3, 54.9, 44.6, 34.3, 28.1, 26.9, 24.9; IR (Neat Film NaCl) 2939,1679, 1604, 1512, 1456, 1281, 1256, 1169, 1139, 1054, 961 cm⁻¹; HRMS(MM: ESI-APCI) m/z calc'd for C₁₉H₂₄NO₅ [M+H]⁺: 346.1649, found346.1642.

Benzoyl Lactam SI18

Benzoyl lactam SI8 was prepared by the acylation and alkylation methodusing 3-morpholinone as a starting material and methyl iodide as analkylating reagent. See Zhou, et al., “Catalytic asymmetric synthesis ofoxindoles bearing a tetrasubstituted stereocenter at the C-3 position,”Adv. Synth. Catal. 1381-1407 (2010), the entire content of which isincorporated herein by reference. Benzoyl lactam S118 was isolated byflash chromatography (SiO₂, 5 to 15% EtOAc in hexanes) as a colorlessoil. R_(f)=0.40 (20% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.70-7.61 (m, 2H), 7.56-7.44 (m, 1H), 7.46-7.33 (m, 2H), 5.98 (ddt,J=17.1, 10.4, 5.9 Hz, 1H), 5.41 (dq, J=17.2, 1.4 Hz, 1H), 5.34 (dq,J=10.4, 1.1 Hz, 1H), 4.76 (dt, J=6.0, 1.3 Hz, 2H), 4.24 (ddd, J=12.4,10.1, 3.2 Hz, 1H), 4.12 (ddd, J=12.4, 4.1, 3.3 Hz, 1H), 4.02 (ddd,J=13.2, 10.1, 4.1 Hz, 1H), 3.91 (dt, J=13.2, 3.3 Hz, 1H), 1.68 (s, 3H);¹³C NMR (126 MHz, CDCl₃) δ 173.0, 169.0 (2C), 134.9, 132.2, 131.0,128.3, 128.1, 119.8, 81.5, 66.8, 61.6, 45.3, 22.2; IR (Neat Film NaCl)2943, 2892, 1749, 1689, 1149, 1375, 1311, 1281, 1246, 1124, 1080, 938,727 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₆H₁₈NO₅ [M+H]⁺: 304.1179,found 304.1171.

Benzoyl Lactam SI19

Benzoyl lactam SI19 was prepared by the acylation and alkylation methodusing Selectfluor as a fluorinating agent. See Amat, et al.,“Enantioselective Synthesis of 3,3-Disubstituted Piperidine Derivativesby Enolate Dialkylation of Phenylglycinol-derived OxazolopiperidoneLactams,” J. Org. Chem. 72, 4431-4439 (2007), the entire content ofwhich is incorporated herein by reference. Benzoyl lactam SI19 wasisolated by flash chromatography (SiO₂, 20 to 35% Et₂O in hexanes) as acolorless oil. R_(f)=0.57 (35% Et₂O in hexanes developed three times);^(1H) NMR (500 MHz, CDCl₃) δ 7.69-7.61 (m, 2H), 7.53-7.45 (m, 1H),7.42-7.34 (m, 2H), 5.94 (ddt, J=17.2, 10.4, 5.9 Hz, 1H), 5.39 (dq,J=17.2, 1.4 Hz, 1H), 5.31 (dq, J=10.4, 1.1 Hz, 1H), 4.76 (dt, J=6.0, 1.3Hz, 2H), 3.98 (dddd, J=12.9, 6.0, 4.7, 1.1 Hz, 1H), 3.80 (dddd, J=14.8,8.8, 4.4, 1.7 Hz, 1H), 2.62-2.45 (m, 1H), 2.45-2.30 (m, 1H), 2.25-2.05(m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 173.8, 166.7 (d, J=26.0 Hz), 166.3(d, J=23.5 Hz), 134.3, 132.3, 130.6, 128.3, 128.2, 119.9, 92.4 (d,J=194.8 Hz), 67.1, 46.2, 31.9 (d, J=22.4 Hz), 18.6 (d, J=4.0 Hz); IR(Neat Film NaCl) 3064, 2956, 1768, 1711, 1691, 1450, 1396, 1304, 1271,1190, 1137, 1102, 994, 944, 912, 726, 694, 658 cm⁻¹; HRMS (MM: ESI-APCI)m/z calc'd for C₁₆H₁₇NO₄F [M+H]⁺: 306.1136, found 306.1131.

Benzoyl Glutarimide SI20

Benzoyl glutarimide SI20 was prepared from glutarimide by a combinationof known methods and diallyl malonate method. See Badillo, et al.,“Enantioselective synthesis of oxindoles and spirooxindoles withapplications in drug discovery,” Curr. Opin. Drug Disc. Dev. 13, 758-776(2010), the entire content of which is incorporated herein by reference.Benzoyl glutarimide SI20 (32 mg, 72% yield) was isolated as a colorlessoil by flash chromatography (SiO₂, 17 to 25% EtOAc in hexanes).R_(f)=0.18 (25% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d,J=8.22 Hz, 2H), 7.62 (t, J=7.46 Hz, 1H), 7.46 (dd, J=8.22, 7.46 Hz, 2H),5.93 (ddt, J=17.2, 10.4, 6.0 Hz, 1H), 5.39 (dq, J=17.2, 1.20 Hz, 1H),5.32 (dq, J=10.4, 1.20 Hz, 1H), 4.75 (ddt, J=12.9, 6.0, 1.20 Hz, 1H),4.71 (ddt, J=12.9, 6.0, 1.20 Hz, 1H), 2.81-2.70 (m, 2H), 2.40 (ddd,J=14.2, 5.13, 3.56 Hz, 1H), 2.10 (ddd, J=14.2, 11.7, 6.36 Hz, 1H), 1.59(s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.1, 170.8, 170.7, 170.4, 134.9,131.6, 130.8, 130.3, 129.0, 120.0, 66.9, 51.0, 30.0, 29.1, 20.8; IR(Neat Film NaCl) 3070, 2943, 2878, 1755, 1716, 1689, 1450, 1240, 1179,975, 781 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₇H₁₈NO₅ [M+H]⁺:316.1179, found 316.1192.

Benzoyl Glutarimide SI21

Benzoyl glutarimide SI121 was prepared from glutarimide by a combinationof known methods and the diallyl malonate method. See Badillo, et al.,“Enantioselective synthesis of oxindoles and spirooxindoles withapplications in drug discovery,” Curr. Opin. Drug Disc. Dev. 13, 758-776(2010), the entire content of which is incorporated herein by reference.Benzoyl glutarimide SI21 (67 mg, 85% yield) was isolated as a colorlessoil by flash chromatography (SiO₂, 17 to 25% EtOAc in hexanes).R_(f)=0.24 (25% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.95 (d,J=8.28 Hz, 2H), 7.62 (t, J=7.46 Hz, 1H), 7.46 (dd, J=8.28, 7.46 Hz, 2H),5.93 (ddt, J=17.0, 10.4, 6.0 Hz, 1H), 5.39 (dq, J=17.0, 1.2 Hz, 1H),5.32 (dq, J=10.4, 1.2 Hz, 1H), 4.77 (ddt, J=12.9, 6.0, 1.2 Hz, 1H), 4.74(ddt, J=12.9, 6.0, 1.2 Hz, 1H), 2.84-2.72 (m, 2H), 2.34 (ddd, J=14.1,5.2, 3.28 Hz, 1H), 2.19 (ddd, J=14.1, 12.2, 5.88 Hz, 1H), 2.15-2.02 (m,2H), 1.01 (t, J=7.44 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.1, 170.4,170.2, 170.1, 134.9, 131.6, 130.8, 130.3, 129.0, 120.0, 66.8, 55.1,29.9, 27.6, 25.6, 8.9; IR (Neat Film NaCl) 3068, 2975, 2884, 1755, 1716,1694, 1450, 1270, 1180, 950, 779 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'dfor C₁₈H₂₀NO₅ [M+H]⁺: 330.1336, found 330.1334.

Acetyl Lactam SI22

Acetyl lactam SI22 was prepared the diallyl malonate method usingdiallyl 2-benzylmalonate as a starting material and acetic anhydride asan acetylating reagent. Acetyl lactam SI22 was isolated by flashchromatography (SiO₂, 5 to 20% EtOAc in hexanes) as a colorless oil.R_(f)=0.46 (20% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.30-7.20(m, 3H), 7.20-7.14 (m, 2H), 5.88 (ddt, J=17.2, 10.4, 5.8 Hz, 1H), 5.33(dq, J=17.2, 1.5 Hz, 1H), 5.27 (dq, J=10.4, 1.2 Hz, 1H), 4.65 (dq,J=5.8, 1.4 Hz, 2H), 3.73-3.62 (m, 1H), 3.53 (d, J=13.6 Hz, 1H), 3.35(ddd, J=13.8, 9.1, 4.8 Hz, 1H), 3.16 (d, J=13.6 Hz, 1H), 2.52 (s, 3H),2.29-2.19 (m, 1H), 1.89-1.71 (m, 2H), 1.70-1.56 (m, 1H); ¹³C NMR (126MHz, CDCl₃) δ 173.9, 172.3, 171.6, 135.8, 131.2, 130.6, 128.3, 127.1,119.3, 66.4, 58.1, 43.6, 41.2, 29.4, 27.2, 19.8; IR (Neat Film NaCl)3063, 3029, 2942, 1733, 1699, 1496, 1455, 1368, 1296, 1234, 1177, 1116,1034, 992, 975, 934, 746, 703 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₁₈H₂₂NO₄ [M+H]⁺: 316.1543, found 316.1541.

Phenyl Carbamate Lactam SI23

Phenyl carbamate lactam SI23 was prepared in a manner analogous to thetosyl lactam of Compound 1a using lactam SI4 and phenyl chloroformate.Phenyl carbamate lactam SI23 was isolated by flash chromatography (SiO₂,5 to 20% EtOAc in hexanes) as a colorless oil. R_(f)=0.42 (50% EtOAc inhexanes); ¹H NMR (500 MHz, CDC13) δ 7.40-7.35 (m, 2H), 7.26-7.21 (m,1H), 7.20-7.16 (m, 2H), 5.91 (ddt, J=17.2, 10.4, 5.6 Hz, 1H), 5.36 (dq,J=17.2, 1.5 Hz, 1H), 5.26 (dq, J=10.5, 1.3 Hz, 1H), 4.77-4.59 (m, 2H),3.90 (ddd, J=12.9, 7.6, 5.3 Hz, 1H), 3.85-3.74 (m, 1H), 2.47 (dddd,J=13.8, 6.2, 5.0, 1.0 Hz, 1H), 2.06-1.86 (m, 2H), 1.80 (ddd, J=14.2,9.3, 5.0 Hz, 1H), 1.56 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.1, 171.2,153.3, 150.8, 131.3, 129.4, 126.0, 121.4, 118.8, 66.2, 53.4, 46.8, 32.7,22.7, 20.1; IR (Neat Film NaCl) 2943, 1786, 1732, 1494, 1457, 1297,1267, 1204, 1161, 1134, 982, 943, 752, 689, 665 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₁₇H₂₀NO₅ [M+H]⁺: 318.1336, found 318.1332.

Benzyl Carbamate Lactam SI24

Benzyl carbamate lactam SI24 was prepared by the acylation andalkylation method using N-benzyloxycarbonylpyrrolidin-2-one as astarting material and methyl iodide as an alkylating reagent. SeeOhmatsu, et al., “Chiral 1,2,3-triazoliums as New Cationic OrganicCatalysts with Anion-Recognition Ability: Application to AsymmetricAlkylation of Oxindoles,” J. Am. Chem. Soc. 133, 1307-1309 (2011), theentire content of which is incorporated herein by reference. Cbz lactamSI24 was isolated by flash chromatography (SiO₂, 5 to 15% EtOAc inhexanes) as a colorless oil. R_(f)=0.40 (20% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.46-7.40 (m, 2H), 7.40-7.28 (m, 3H), 5.87 (ddt,J=17.1, 10.4, 5.6 Hz, 1H), 5.30 (dq, J=17.2, 1.5 Hz, 1H) 5.30 (s, 2H),5.23 (dq, J=10.5, 1.2 Hz, 1H), 4.69-4.55 (m, 2H), 3.82 (ddq, J=10.7,8.4, 5.8 Hz, 2H), 2.54 (ddd, J=13.1, 7.4, 4.2 Hz, 1H), 1.93 (dt, J=13.2,8.3 Hz, 1H), 1.50 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.9, 170.7,151.4, 135.1, 131.3, 128.6, 128.4, 128.1, 118.8, 68.3, 66.3, 53.3, 43.7,30.5, 20.2; IR (Neat Film NaCl) 2984, 2939, 1793, 1758, 1725, 1456,1383, 1300, 1202, 1138, 1009, 983, 774, 739, 698 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₁₇H₂₀NO₅ [M+H]⁺: 318.1336, found 318.1136.

4-Phenylbenzoyl Lactam SI25

4-phenylbenzoyl lactam SI25 was prepared the diallyl malonate methodusing lactam SI4 and 4-phenylbenzoyl chloride. 4-Phenylbenzoyl lactamSI25 was isolated by flash chromatography (SiO₂, 5 to 15% EtOAc inhexanes) as an off-white solid. R_(f)=0.27 (20% EtOAc in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 7.84-7.77 (m, 2H), 7.65-7.54 (m, 4H), 7.49-7.40(m, 2H), 7.40-7.34 (m, 1H), 6.00 (ddt, J=17.2, 10.4, 5.9 Hz, 1H), 5.41(dq, J=17.2, 1.5 Hz, 1H), 5.34 (dq, J=10.4, 1.2 Hz, 1H), 4.75 (dt,J=5.9, 1.3 Hz, 2H), 3.95-3.84 (m, 1H), 3.81 (ddt, J=12.9, 5.1, 1.4 Hz,1H), 2.52 (dddd, J=13.8, 5.7, 4.3, 1.4 Hz, 1H), 2.10-1.94 (m, 2H),1.90-1.76 (m, 1H), 1.52 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.7,172.9, 172.5, 144.5, 140.3, 134.5, 131.4, 128.8, 128.7, 127.8, 127.3,126.8, 119.5, 66.5, 52.9, 46.89, 33.8, 22.5, 20.3; IR (Neat Film NaCl)3030, 2942, 2874, 1733, 1679, 1607, 1486, 1449, 1389, 1278, 1191, 1139,939, 749, 698 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₂₃H₂₄NO₄ [M+H]⁺:378.1700, found 378.1708.

1-Naphthoyl Lactam SI26

1-naphthoyl lactam SI26 was prepared by the diallyl malonate methodusing lactam SI4 and 1-naphthoyl chloride. 1-Naphthoyl lactam SI26 wasisolated by flash chromatography (SiO₂, 10 to 20% EtOAc in hexanes) as acolorless oil. R_(f)=0.50 (35% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 8.07-8.01 (m, 1H), 7.90 (dd, J=8.2, 1.4 Hz, 1H), 7.88-7.83 (m,1H), 7.57-7.47 (m, 3H), 7.42 (td, J=7.6, 7.0, 1.2 Hz, 1H), 5.99-5.86 (m,1H), 5.35 (dq, J=17.3, 1.3 Hz, 1H), 5.30 (dq, J=10.6, 1.0 Hz, 1H), 4.66(ddt, J=5.4, 4.2, 1.3 Hz, 2H), 4.13-3.91 (m, 2H), 2.49 (ddd, J=13.6,6.1, 4.5 Hz, 1H), 2.14-1.97 (m, 2H), 1.83 (ddd, J=14.3, 9.9, 4.6 Hz,1H), 1.42 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.8, 172.4, 172.1,134.9, 133.6, 131.3, 130.3, 129.8, 128.4, 127.0, 126.1, 124.9, 124.4,123.9, 119.3, 66.3, 52.9, 45.7, 33.4, 22.4, 20.1; IR (Neat Film NaCl)3050, 2984, 2942, 1737, 1704, 1682, 1509, 1456, 1387, 1290, 1254, 1194,1144, 1130, 935, 806, 783 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₂₁H₂₂NO₄ [M+H]⁺: 352.1543, found 352.1542.

2-Naphthoyl Lactam SI27

2-naphthoyl lactam SI27 was prepared by the diallyl malonate methodusing lactam SI4 and 2-naphthoyl chloride. 2-Naphthoyl lactam SI27 wasisolated by flash chromatography (SiO₂, 20 to 33% Et₂O in hexanes) as acolorless oil. R_(f)=0.25 (35% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃)δ 8.30 (t, J=1.2 Hz, 1H), 7.90 (dd, J=8.1, 1.4 Hz, 1H), 7.85-7.79 (m,2H), 7.76 (dd, J=8.6, 1.7 Hz, 1H), 7.54 (ddd, J=8.1, 6.8, 1.4 Hz, 1H),7.50 (ddd, J=8.1, 6.9, 1.4 Hz, 1H), 6.01 (ddt, J=17.2, 10.4, 5.8 Hz,1H), 5.42 (dq, J=17.2, 1.4 Hz, 1H), 5.34 (dq, J=10.4, 1.1 Hz, 1H), 4.77(dt, J=5.9, 1.3 Hz, 2H), 3.93 (ddd, J=12.8, 8.9, 5.3 Hz, 1H), 3.85 (ddt,J=12.9, 5.1, 1.3 Hz, 1H), 2.52 (dddd, J=13.8, 5.6, 4.2, 1.3 Hz, 1H),2.12-1.93 (m, 2H), 1.84 (ddd, J=13.7, 10.2, 4.7 Hz, 1H), 1.51 (s, 3H);¹³C NMR (126 MHz, CDCl₃) δ 174.9, 172.8, 172.5, 134.8, 133.2, 132.5,131.4, 129.2, 129.0, 127.7 (2C), 127.6, 126.3, 124.4, 119.4, 66.4, 52.9,46.8, 33.7, 22.4, 20.2; IR (Neat Film NaCl) 3059, 2941, 2873, 1730,1680, 1456, 1385, 1285, 1234, 1186, 1131, 936, 778, 762 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₂₁H₂₂NO₄ [M+H]⁺: 352.1543, found 352.1530.

General Procedure for Preparative Allylic Alkylation Reactions to FormN-acyl Lactam Derivatives

The N-acyl lactam substrates described above were subjected to allylicalkylation reactions to form N-acyl lactam derivative building blockcompounds. The general procedure for these reactions is described here.

In a nitrogen-filled glovebox, an oven-dried 20 mL vial was charged withPd₂pmdba₃ (27.4 mg, 0.025 mmol, 0.05 equiv) or Pd₂dba₃ (22.9 mg, 0.025mmol, 0.05 equiv), (S)-(CF₃)₃-t-BuPHOX (37.0 mg, 0.0625 mmol, 0.125equiv), toluene (15 mL or 13 mL if the substrate is an oil), and amagnetic stir bar. See Franckevicius, et al., “AsymmetricDecarboxylative Alkylation of Oxindoles,” Org. Lett. 13, 4264-4267(2011), the entire content of which is incorporated herein by reference.The vial was stirred at ambient glovebox temperature (˜28° C.) for 30min and the substrate (0.50 mmol, 1.00 equiv) was added either as asolid or as a solution of an oil dissolved in toluene (2 mL). The vialwas sealed and heated to 40° C. When complete consumption of thestarting material was observed by colorimetric change (from light greento red-orange) and confirmed by thin layer chromatography on SiO₂, thereaction mixtures were removed from the glovebox, concentrated underreduced pressure, and purified by flash chromatography to afford thedesired alkylated product.

Characterization Data for the N-acyl Lactam Derivative Building Blocks

The N-acyl lactam Derivatives were isolated as described below andcharacterized. The characterization data is reported below.

Benzoyl Lactam 3

See Jakubec, et al., “Cyclic Imine Nitro-Mannich/Lactamization Cascades:A Direct Stereoselective Synthesis of Multicyclic PiperidinoneDerivatives,” Org. Lett. 10, 4267-4270 (2008), the entire content ofwhich is incorporated by reference. Benzoyl lactam 3 was isolated byflash chromatography (SiO₂, 15 to 20% Et₂O in hexanes) as a colorlessoil. 97.2% yield. R_(f)=0.39 (20% Et₂O in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.53-7.49 (m, 2H), 7.48-7.43 (m, 1H), 7.41-7.34 (m, 2H), 5.74(dddd, J=16.7, 10.4, 7.6, 7.0 Hz, 1H), 5.19-5.02 (m, 2H), 3.84-3.70 (m,2H), 2.51 (ddt, J=13.8, 7.0, 1.3 Hz, 1H), 2.28 (ddt, J=13.8, 7.6, 1.2Hz, 1H), 2.06-1.91 (m, 2H), 1.91-1.74 (m, 3H), 1.74-1.63 (m, 1H), 0.91(t, J=7.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 178.0, 175.6, 136.7,133.6, 131.2, 128.1, 127.4, 118.6, 47.4, 46.9, 41.3, 30.3 (2C), 19.6,8.3; IR (Neat Film NaCl) 3072, 2970, 2941, 2880, 1678, 1448, 1384, 1283,1147, 916, 725, 694 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₇H₂₂NO₂[M+H]⁺: 272.1645, found 272.1649; [α]D²⁵ −28.6° (c 1.15, CHCl₃, 99% ee).

Benzoyl Lactam 4

See Jakubec, et al., “Cyclic Imine Nitro-Mannich/Lactamization Cascades:A Direct Stereoselective Synthesis of Multicyclic PiperidinoneDerivatives,” Org. Lett. 10, 4267-4270 (2008), the entire content ofwhich is incorporated by reference. Benzoyl lactam 4 was isolated byflash chromatography (SiO₂, 10% Et₂O in hexanes) as a white solid. 84.8%yield. R_(f)=0.48 (35% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.54(dd, J=8.1, 1.4 Hz, 2H), 7.52-7.46 (m, 1H), 7.43-7.37 (m, 2H), 7.32-7.22(m, 3H), 7.18-7.11 (m, 2H), 5.80 (dddd, J=16.8, 10.1, 7.6, 6.8 Hz, 1H),5.21-5.06 (m, 2H), 3.70 (ddd, J=12.2, 7.0, 4.8 Hz, 1H), 3.63 (ddd,J=12.5, 7.7, 4.4 Hz, 1H), 3.34 (d, J=13.4 Hz, 1H), 2.73-2.64 (m, 1H),2.68 (d, J=13.3 Hz, 1H), 2.25 (ddt, J=13.8, 7.7, 1.1 Hz, 1H), 2.03-1.91(m, 1H), 1.91-1.83 (m, 1H), 1.81 (dd, J=6.7, 5.3 Hz, 2H); ¹³C NMR (126MHz, CDCl₃) δ 177.4, 175.5, 136.9, 136.6, 133.2, 131.4, 130.8, 128.2,128.1, 127.6, 126.7, 119.3, 48.8, 46.8, 43.0, 42.9, 28.9, 19.6; IR (NeatFilm NaCl) 3061, 3028, 2942, 1679, 1449, 1286, 1149, 919, 724, 704, 695cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₂₂H₂₄NO₂ [M+H]⁺: 334.1802,found 334.1800; [α]D²⁵ +48.1° (c 0.825, CHCl₃, 99% ee).

Benzoyl Lactam 5

Benzoyl lactam 5 was isolated by flash chromatography (SiO₂, 25% Et₂O inhexanes) as a light yellow oil. 91.8% yield. R_(f)=0.39 (35% Et₂O inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.53-7.49 (m, 2H), 7.49-7.44 (m,1H), 7.41-7.31 (m, 2H), 5.72 (ddt, J=17.4, 10.3, 7.3 Hz, 1H), 5.23-5.05(m, 2H), 3.78 (t, J=6.0 Hz, 2H), 3.67 (s, 3H), 2.58-2.47 (m, 1H),2.42-2.24 (m, 3H), 2.08-1.97 (m, 4H), 1.93 (ddd, J=14.0, 7.8, 4.6 Hz,1H), 1.78 (ddd, J=13.9, 7.1, 4.9 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ177.4, 175.5, 173.7, 136.5, 132.6, 131.4, 128.2, 127.4, 119.4, 51.7,47.0, 46.6, 41.2, 32.2, 31.2, 29.0, 19.4; IR (Neat Film NaCl) 3073,2950, 2874, 1736, 1679, 1448, 1281, 1150, 920, 727, 696, 665 cm⁻¹; HRMS(MM: ESI-APCI) m/z calc'd for C₁₉H₂₄NO₄ [M+H]⁺: 330.1700, found330.1704; [α]D²⁵ +14.0° (c 0.72, CHCl₃, 99% ee).

Benzoyl Lactam 6

Benzoyl lactam 6 was isolated by flash chromatography (SiO₂, 15 to 25%EtOAc in hexanes) as a colorless oil. 88.2% yield. R_(f)=0.43 (35% EtOAcin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.52-7.47 (m, 3H), 7.41 (ddt,J=8.7, 6.6, 1.0 Hz, 2H), 5.71 (ddt, J=17.4, 10.1, 7.3 Hz, 1H), 5.28-5.15(m, 2H), 3.88-3.79 (m, 1H), 3.76 (ddd, J=12.9, 8.7, 4.2 Hz, 1H), 2.57(ddt, J=14.1, 7.3, 1.2 Hz, 1H), 2.44-2.29 (m, 3H), 2.13-2.04 (m, 2H),2.03-1.89 (m, 3H), 1.87-1.78 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.8,175.2, 136.2, 131.7, 131.5, 128.3, 127.3, 120.3, 119.5, 47.0, 46.5,41.1, 32.7, 30.8, 19.2, 12.5; IR (Neat Film NaCl) 3074, 2945, 2876,1678, 1448, 1389, 1282, 1151, 922, 727, 696 cm⁻¹; HRMS (MM: ESI-APCI)m/z calc'd for C₁₈H₂₁N₂O₂ [M+H]⁺: 297.1598, found 297.1603; [α]D²⁵+46.9° (c 0.83, CHCl₃, 99% ee).

Benzoyl Lactam 7

Benzoyl lactam 7 was isolated by flash chromatography (SiO₂, 5 to 15%Et₂O in hexanes) as a colorless oil. 85.4% yield. R_(f)=0.32 (10% Et₂Oin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.54-7.48 (m, 2H), 7.48-7.42 (m,1H), 7.41-7.33 (m, 2H), 5.76 (ddt, J=17.3, 10.2, 7.3 Hz, 1H), 5.18-5.06(m, 2H), 3.81-3.75 (m, 2H), 3.75-3.64 (m, 2H), 2.55 (ddt, J=13.8, 7.1,1.2 Hz, 1H), 2.33 (ddt, J=13.8, 7.5, 1.1 Hz, 1H), 2.10-1.94 (m, 4H),1.94-1.85 (m, 1H), 1.81 (ddd, J=13.9, 7.3, 5.6 Hz, 1H), 0.88 (s, 9H),0.04 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 177.6, 175.5, 136.8, 133.4,131.2, 128.1, 127.4, 118.9, 59.2, 46.9, 46.3, 42.2, 39.7, 30.8, 25.9,19.6, 18.2, −5.4; IR (Neat Film NaCl) 2953, 2928, 2884, 2856, 1681,1280, 1257, 1151, 1093, 836, 776, 725, 694 cm⁻¹; HRMS (MM: ESI-APCI) m/zcalc'd for C₂₃H₃₆NO₃Si [M+H]⁺: 402.2459, found 402.2467; [α]D²⁵ −3.71°(c 1.40, CHCl₃, 96% ee).

Benzoyl Lactam 8

Benzoyl lactam 8 was isolated by flash chromatography (SiO₂, 5 to 9%EtOAc in hexanes) as a colorless oil. 78.0% yield. R_(f)=0.54 (25% EtOAcin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.54-7.50 (m, 2H), 7.48-7.43 (m,1H), 7.41-7.35 (m, 2H), 4.89 (t, J=1.8 Hz, 1H), 4.70 (dt, J=2.1, 1.0 Hz,1H), 3.94-3.84 (m, 1H), 3.74-3.63 (m, 1H), 2.75 (dd, J=13.8, 1.3 Hz,1H), 2.13 (dd, J=13.8, 0.8 Hz, 1H), 2.08-1.94 (m, 3H), 1.69 (s, 3H),1.68-1.61 (m, 1H), 1.37 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 178.8,175.5, 141.9, 136.5, 131.3, 128.1, 127.4, 115.5, 47.2, 46.2, 44.0, 32.9,26.9, 24.7, 19.8; IR (Neat Film NaCl) 3070, 2940, 1678, 1448, 1274,1144, 726 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₇H₂₂NO₂ [M+H]⁺:272.1645, found 272.1655; [α]D²⁵ −105.6° (c 0.99, CHCl₃, 97% ee).

Benzoyl Lactam 9

Benzoyl lactam 9 was isolated by flash chromatography (SiO₂, 8 to 10%Et₂O in hexanes) as a colorless oil. 60.3% yield. R_(f)=0.39 (25% EtOAcin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.55-7.49 (m, 2H), 7.49-7.43 (m,1H), 7.42-7.34 (m, 2H), 5.32 (d, J=1.7 Hz, 1H), 5.18 (s, 1H), 3.92 (ddt,J=12.7, 4.8, 1.7 Hz, 1H), 3.75-3.66 (m, 1H), 3.04 (dd, J=14.5, 1.0 Hz,1H), 2.50 (d, J=14.5 Hz, 1H), 2.16 (ddd, J=13.4, 10.2, 4.4 Hz, 1H),2.12-1.98 (m, 2H), 1.86-1.77 (m, 1H), 1.43 (s, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 177.9, 175.3, 138.3, 136.4, 131.4, 128.1, 127.4, 117.1, 47.0(2C), 44.2, 32.8, 26.3, 19.7; IR (Neat Film NaCl) 2944, 2872, 1679,1628, 1448, 1386, 1277, 1151, 894, 726 cm⁻¹; HRMS (MM: ESI-APCI) m/zcalc'd for C₁₆H₁₉NO₂Cl [M+H]⁺: 292.1099, found 292.1102; [α]D²⁵ −91.4°(c 0.94, CHCl₃, 95% ee).

Benzoyl Lactam 10

Benzoyl lactam 10 was isolated by flash chromatography (SiO₂, 5 to 10%Et₂O in hexanes) as a colorless oil. 90.3% yield. R_(f)=0.35 (35% Et₂Oin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.58-7.54 (m, 2H), 7.53-7.48 (m,1H), 7.43-7.38 (m, 2H), 5.78 (dddd, J=17.1, 10.2, 7.8, 7.0 Hz, 1H),5.22-5.09 (m, 2H), 3.87 (dd, J=7.7, 6.7 Hz, 2H), 2.36 (dd, J=13.8, 7.0Hz, 1H), 2.24 (dd, J=13.7, 7.8 Hz, 1H), 2.15 (dt, J=12.9, 7.6 Hz, 1H),1.85 (dt, J=13.1, 6.7 Hz, 1H), 1.22 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ178.6, 170.8, 134.4, 133.0, 131.8, 128.8, 127.7, 119.3, 46.2, 42.8,41.8, 29.3, 22.8; IR (Neat Film NaCl) 3075, 2974, 2902, 1742, 1674,1448, 1377, 1357, 1306, 1243, 1156, 921, 860, 731, 694, 656 cm⁻¹; HRMSESI-APCI) m/z calc'd for C₁₄H₁₈NO₂ [M+H]⁺: 244.1332, found 244.1336;[α]D²⁵ −31.6° (c 1.04, CHCl₃, 98% ee).

Benzoyl Lactam 11

Benzoyl lactam 11 was isolated by flash chromatography (SiO₂, 10 to 20%Et₂O in hexanes) as a colorless oil. 89.3% yield. R_(f)=0.24 (20% Et₂Oin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.60-7.56 (m, 2H), 7.56-7.51 (m,1H), 7.49-7.45 (m, 2H), 7.42 (ddt, J=7.8, 6.7, 1.0 Hz, 2H), 7.31 (d,J=7.7 Hz, 2H), 5.83 (dddd, J=17.1, 10.1, 7.8, 6.9 Hz, 1H), 5.28-5.10 (m,2H), 3.70 (dt, J=11.4, 7.5 Hz, 1H), 3.39 (dt, J=11.4, 6.9 Hz, 1H), 3.10(d, J=13.4 Hz, 1H), 2.76 (d, J=13.5 Hz, 1H), 2.48 (dd, J=13.8, 7.0 Hz,1H), 2.32 (dd, J=13.8, 7.8 Hz, 1H), 2.05 (t, J=7.3 Hz, 2H); ¹³C NMR (126MHz, CDCl₃) δ 177.1, 170.5, 140.9, 134.2, 132.3, 131.9, 130.7, 129.4 (q,J_(C-F)=32.5 Hz), 128.7, 127.7, 125.3 (q, J_(C-F)=3.7 Hz), 124.1 (q,J_(C-F)=272.2 Hz), 120.1, 51.3, 43.0, 41.9 (2C), 25.2; IR (Neat FilmNaCl) 3080, 2977, 2913, 1738, 1677, 1325, 1294, 1244, 1164, 1121, 1067,859, 728, 701, 665 cm⁻¹; HRMS (FAB) m/z calc'd for C₂₂H₂₁NO₂F₃ [M+H]⁺:388.1524, found 388.1525; [α]D²⁵ +78.3° (c 1.90, CHCl₃, 93% ee).

Benzoyl Lactam 12

Benzoyl lactam 12 was isolated by flash chromatography (SiO₂, 10 to 20%Et₂O in hexanes) as a white solid. 85.7% yield. R_(f)=0.35 (35% Et₂O inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.63-7.58 (m, 2H), 7.58-7.52 (m,1H), 7.49-7.40 (m, 2H), 5.87-5.73 (m, 1H), 5.32-5.20 (m, 2H), 4.00 (ddd,J=11.5, 7.7, 6.5 Hz, 1H), 3.90-3.80 (m, 1H), 2.81-2.70 (m, 1H),2.62-2.48 (m, 1H), 2.46-2.27 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 170.3,169.7 (d, JC-F =23.1 Hz), 133.4, 132.4, 129.7 (d, J_(C-F)=7.1 Hz),129.0, 127.9, 121.0, 97.0 (d, J_(C-F)=185.4 Hz), 42.0 (d, J_(C-F)=2.3Hz), 38.4 (d, J_(C-F)=25.2 Hz), 28.5 (d, J_(C-F)=22.6 Hz); IR (Neat FilmNaCl) 3076, 1760, 1676, 1365, 1314, 1253, 1132, 1058, 1008, 980, 920,863, 791, 729 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₄H₁₅NO₂F[M+H]⁺: 248.1081, found 248.1092; [α]D²⁵ −120.5° (c 1.11, CHCl₃, 98%ee).

4-Methoxybenzoyl Lactam 13:

The reaction was performed in MTBE at 40° C. 4-Methoxybenzoyl lactam 13was isolated by flash chromatography (SiO₂, 8% Et₂O in hexanes) as acolorless oil. 83.2% yield. R_(f)=0.48 (25% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.56-7.48 (m, 2H), 6.91-6.82 (m, 2H), 5.86-5.66 (m,1H), 5.18-5.02 (m, 2H), 4.03 (ddd, J=15.0, 8.0, 2.4 Hz, 1H), 3.88 (ddd,J=15.1, 8.5, 2.1 Hz, 1H), 3.83 (s, 3H), 2.50 (ddt, J=13.6, 7.0, 1.2 Hz,1H), 2.35 (ddt, J=13.7, 7.6, 1.1 Hz, 1H), 1.92-1.77 (m, 4H), 1.77-1.62(m, 2H), 1.31 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 182.3, 174.7, 162.2,133.9, 130.0, 128.9, 118.6, 113.5, 55.4, 47.7, 44.7, 43.0, 35.1, 28.2,25.0, 23.4; IR (Neat Film NaCl) 3074, 2932, 1673, 1605, 1511, 1279,1255, 1168, 1112, 1025, 837 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC_(1*)H₂₄NO₃ [M+H]⁺: 302.1751, found 302.1744; [α]D²⁵ −34.7° (c 0.75,CHCl₃, 93% ee).

Benzoyl Lactam 14

Benzoyl lactam 14 was isolated by flash chromatography (SiO₂, 10 to 20%Et₂O in hexanes) as a colorless oil. 91.4% yield. R_(f)=0.36 (35% Et₂Oin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.55-7.52 (m, 2H), 7.52-7.47 (m,1H), 7.42-7.37 (m, 2H), 5.90 (ddt, J=17.3, 10.3, 7.2 Hz, 1H), 5.26-5.10(m, 2H), 4.12-3.95 (m, 3H), 3.94-3.81 (m, 1H), 2.71 (ddt, J=14.1, 7.3,1.2 Hz, 1H), 2.47 (ddt, J=14.1, 7.0, 1.3 Hz, 1H), 1.48 (s, 3H); ¹³C NMR(126 MHz, CDCl₃) 6 174.3, 173.1, 135.7, 132.1, 131.7, 128.1, 127.7,119.3, 80.3, 59.4, 45.7, 43.1, 23.3; IR (Neat Film NaCl) 3075, 2978,2894, 1685, 1448, 1373, 1283, 1227, 1111, 1092, 921, 726, 694 cm⁻¹; HRMS(FAB) m/z calc'd for C₁₅H₁₈NO₃ [M+H]⁺: 260.1287, found 260.1277; [α]D²⁵−72.1° (c 0.97, CHCl₃, 99% ee).

Benzoyl Lactam 15

Benzoyl lactam 15 was isolated by flash chromatography (SiO₂, 5 to 10%EtOAc in hexanes) as a colorless oil. 88.8% yield. R_(f)=0.35 (35% Et₂Oin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.62-7.57 (m, 2H), 7.53-7.47 (m,1H), 7.44-7.37 (m, 2H), 5.87-5.70 (m, 1H), 5.28-5.15 (m, 2H), 3.91(dddd, J=12.8, 6.0, 4.7, 1.4 Hz, 1H), 3.74 (dddd, J=13.6, 9.2, 4.5, 2.4Hz, 1H), 2.86-2.60 (m, 2H), 2.33-2.14 (m, 2H), 2.13-1.89 (m, 2H); ¹³CNMR (126 MHz, CDCl₃) δ 174.5, 170.8 (d, J_(C-F)=23.5 Hz), 135.0, 132.0,130.6 (d, J_(C-F)=6.5 Hz), 128.3, 128.0, 120.4, 93.9 (d, J_(C-F)=179.3Hz), 46.4, 40.0 (d, J_(C-F)=23.6 Hz), 32.1 (d, J_(C-F)=22.5 Hz), 19.1(d, J_(C-F)=4.6 Hz); IR (Neat Film NaCl) 3078, 2956, 1715, 1687, 1478,1449, 1435, 1390, 1288, 1273, 1175, 1152, 1000, 930, 725, 694, 662 cm⁻¹;HRMS (MM: ESI-APCI) m/z calc'd for C₁₅H₁₆NO₂F [M+H]⁺: 262.1238, found262.1244; [α]D²⁵ −120.6° (c 1.09, CHCl₃, 99% ee).

Benzoyl Glutarimide 16

Benzoyl glutarimide 16 was isolated by flash chromatography (SiO₂, 17 to25% EtOAc in hexanes) as a colorless oil. 81% yield. R_(f)=0.21 (25%EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.83 (d, J=8.29 Hz, 2H),7.63 (t, J=7.45 Hz, 1H), 7.48 (dd, J=8.29, 7.45 Hz, 2H), 5.77 (dddd,J=17.4, 10.2, 7.4, 7.0 Hz, 1H), 5.22-5.16 (m, 2H), 2.87-2.77 (m, 2H),2.59 (ddt, J=13.8, 7.0, 1.0 Hz, 1H), 2.40 (ddt, J=13.8, 7.4, 1.0 Hz,1H), 2.12 (ddd, J=14.2, 7.73, 6.81 Hz, 1H), 1.85 (ddd, J=14.2, 6.5, 6.1Hz, 1H), 1.37 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.6, 171.6, 170.9,134.8, 132.0, 131.9, 130.0, 129.1, 120.0, 41.9, 41.7, 29.2, 28.2, 22.8;IR (Neat Film NaCl) 3077, 2975, 2935, 1750, 1713, 1683, 1450, 1340,1239, 1198, 981, 776 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₆H₁₈NO₃[M+H]⁺: 272.1281, found 272.1281; [α]D²⁵ −31.3° (c 1.00, CHCl₃, 94% ee).

Benzoyl Glutarimide 17

Benzoyl glutarimide 17 was isolated by flash chromatography (SiO₂, 17 to25% EtOAc in hexanes) as a colorless oil. 86% yield. R_(f)=0.24 (25%EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.83 (d, J=8.38 Hz, 2H),7.64 (t, J=7.46 Hz, 1H), 7.48 (dd, J=8.38, 7.46 Hz, 2H), 5.75 (dddd,J=17.2, 10.2, 7.7, 7.0 Hz, 1H), 5.20-5.15 (m, 2H), 2.86-2.76 (m, 2H),2.60 (ddt, J=14.0, 7.0, 1.1 Hz, 1H), 2.37 (ddt, J=14.0, 7.7, 1.1 Hz,1H), 2.05 (ddd, J=14.3, 7.85, 6.81 Hz, 1H), 1.97 (ddd, J=14.3, 6.56,6.24 Hz, 1H), 1.87-1.75 (m, 2H), 0.97 (t, J=7.46, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 175.9, 171.6, 171.0, 134.8, 132.4, 131.9, 130.0, 129.0, 119.8,45.4, 39.3, 29.0, 28.1, 25.4, 8.1; IR (Neat Film NaCl) 3076, 2974, 2940,2882, 1750, 1713, 1683, 1450, 1340, 1239, 1195, 1001, 923, 778 cm⁻¹;HRMS (MM: ESI-APCI) m/z calc'd for C₁₇H₂₀NO₃ [M+H]⁺: 286.1438, found286.1432; [α]D²⁵ −16.2° (c 1.00, CHCl₃, 96% ee).

Acyl Lactam 18

Acyl lactam 18 was isolated by flash chromatography (SiO₂, 10 to 20%Et₂O in hexanes) as a colorless oil. 88.4% yield. R_(f)=0.40 (35% Et₂Oin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.32-7.17 (m, 3H), 7.17-7.09 (m,2H), 5.77 (dddd, J=17.0, 10.3, 7.9, 6.8 Hz, 1H), 5.19-5.05 (m, 2H),3.60-3.48 (m, 1H), 3.44 (dddd, J=13.0, 7.0, 4.6, 1.0 Hz, 1H), 3.27 (d,J=13.3 Hz, 1H), 2.68 (d, J=13.2 Hz, 1H), 2.66-2.62 (m, 1H), 2.51 (s,3H), 2.23 (ddt, J=13.5, 7.9, 1.1 Hz, 1H), 1.90-1.61 (m, 3H), 1.57-1.38(m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 178.0, 174.2, 137.1, 133.2, 130.4,128.3, 126.8, 119.2, 49.7, 45.1, 44.8, 44.5, 29.0, 27.6, 19.6; IR (NeatFilm NaCl) 3028, 2941, 1691, 1367, 1291, 1247, 111178, 1131, 1031, 923cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₇H₂₂NO₂ [M+H]⁺: 272.1645,found 272.1646; [α]D²⁵ +11.4° (c 1.03, CHCl₃, 88% ee).

Phenyl Carbamate Lactam 19

Phenyl Carbamate lactam 19 was isolated by flash chromatography (SiO₂,10 to 20% Et₂O in hexanes) as a colorless oil. 82.2% yield. R_(f)=0.39(35% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.35 (m, 2H),7.25-7.21 (m, 1H), 7.20-7.15 (m, 2H), 5.79 (dddd, J=16.7, 10.4, 7.8, 7.0Hz, 1H), 5.18-5.08 (m, 2H), 3.89-3.82 (m, 1H), 3.78-3.70 (m, 1H), 2.55(ddt, J=13.6, 7.0, 1.2 Hz, 1H), 2.33 (ddt, J=13.6, 7.8, 1.1 Hz, 1H),2.00-1.85 (m, 3H), 1.70-1.59 (m, 1H), 1.30 (s, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 177.3, 153.8, 150.8, 133.3, 129.3, 125.9, 121.5, 118.9, 48.2,45.0, 44.1, 33.0, 25.3, 19.6; IR (Neat Film NaCl) 3074, 2939, 2870,1783, 1733, 1718, 1494, 1299, 1265, 1203, 1153, 991, 920 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₁₆H₂₀NO₃ [M+H]⁺: 274.1438, found 274.1444;[α]D²⁵ −81.6° (c 1.11, CHCl₃, 94% ee).

Benzyl Carbamate Lactam 20

Benzyl carbamate lactam 20 was isolated by flash chromatography (SiO₂,10 to 30% Et₂O in hexanes) as a colorless oil. 85.9% yield. R_(f)=0.41(35% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.46-7.42 (m, 2H), 7.37(ddd, J=7.4, 6.3, 1.5 Hz, 2H), 7.35-7.30 (m, 1H), 5.74 (dddd, J=15.9,11.0, 7.9, 6.9 Hz, 1H), 5.28 (s, 2H), 5.18-5.06 (m, 2H), 3.77-3.63 (m,2H), 2.33 (ddt, J=13.8, 6.9, 1.2 Hz, 1H), 2.24 (ddt, J=13.8, 7.9, 1.0Hz, 1H), 2.03 (ddd, J=12.9, 8.1, 6.9 Hz, 1H), 1.74 (ddd, J=13.2, 7.7,5.9 Hz, 1H), 1.19 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 178.0, 151.7,135.3, 133.0, 128.6, 128.3, 128.1, 119.1, 68.0, 45.5, 42.9, 41.7, 29.5,22.6; IR (Neat Film NaCl) 3066, 2973, 2930, 2903, 1789, 1750, 1719,1456, 1380, 1363, 1301, 1217, 1001, 919, 776, 736 cm⁻¹; HRMS (MM:ESI-APCI) m/z calc'd for C₁₆H₂₀NO₃[M+H]⁺: 274.1438, found 274.1438;[α]D²⁵ −41.4° (c 1.02, CHCl₃, 91% ee).

4-Phenylbenzoyl Lactam 21

4-Phenylbenzoyl lactam 21 was isolated by flash chromatography (SiO₂, 10to 15% Et₂O in pentane) as a colorless oil. 84.6% yield. R_(f)=0.43 (35%Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.64-7.57 (m, 6H), 7.45(ddd, J=7.8, 6.7, 1.1 Hz, 2H), 7.40-7.34 (m, 1H), 5.84-5.70 (m, 1H),5.20-5.09 (m, 2H), 3.91-3.82 (m, 1H), 3.74 (ddd, J=12.1, 7.4, 5.7 Hz,1H), 2.59 (ddd, J=13.7, 7.0, 1.3 Hz, 1H), 2.32 (ddt, J=13.7, 7.7, 1.2Hz, 1H), 2.10-1.91 (m, 3H), 1.77-1.64 (m, 1H), 1.34 (s, 3H); ¹³C NMR(126 MHz, CDCl₃) δ 179.1, 175.1, 144.2, 140.2, 135.1, 133.3, 128.8,128.1, 127.8, 127.2, 126.9, 119.0, 47.2, 44.0, 43.3, 33.3, 25.2, 19.5;IR (Neat Film NaCl) 3073, 2938, 2869, 1677, 1607, 1478, 1383, 1295,1279, 1145, 922, 849, 743, 698 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₂₂H₂₄NO_(2 [)M+H]⁺: 334.1802, found 334.1812; [α]D²⁵ −82.6° (c 0.75,CHCl₃, 99% ee).

1-Naphthoyl Lactam 22

1-Naphthoyl lactam 22 was isolated by flash chromatography (SiO₂, 10 to20% Et₂O in hexanes) as a white solid. 86.3% yield. R_(f)=0.42 (35% Et₂Oin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 8.03-7.97 (m, 1H), 7.90-7.83 (m,2H), 7.55-7.46 (m, 2H), 7.42 (dd, J=8.1, 7.1 Hz, 1H), 7.37 (dd, J=7.1,1.3 Hz, 1H), 5.64 (dddd, J=17.2, 10.2, 7.6, 7.1 Hz, 1H), 5.16-4.97 (m,2H), 4.05 (dddd, J=12.8, 6.3, 5.2, 1.3 Hz, 1H), 3.95-3.82 (m, 1H), 2.43(ddt, J=13.7, 7.1, 1.2 Hz, 1H), 2.19 (ddt, J=13.7, 7.6, 1.1 Hz, 1H),2.11-1.99 (m, 2H), 1.99-1.91 (m, 1H), 1.73-1.64 (m, 1H), 1.18 (s, 3H);¹³C NMR (126 MHz, CDCl₃) δ 178.5, 174.3, 135.8, 133.6, 133.1, 130.0,129.8, 128.4, 126.9, 126.2, 124.9, 124.5, 123.3, 118.9, 46.4, 44.1,43.3, 33.2, 24.8, 19.5; IR (Neat Film NaCl) 3062, 2937, 2869, 1702,1677, 1381, 1295, 1251, 1147, 923, 781 cm⁻¹; HRMS (MM: ESI-APCI) m/zcalc'd for C₂₀H₂₂NO₂ [M+H]⁺: 308.1645, found 308.1648; [α]D²⁵ −102.3° (c1.12, CHCl₃, 99% ee).

2-Naphthoyl Lactam 23

2-Naphthoyl lactam 23 was isolated by flash chromatography (SiO₂, 10 to20% Et₂O in hexanes) as a colorless oil. 82.1% yield. R_(f)=0.42 (35%Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 8.10 (dd, J=1.8, 0.8 Hz,1H), 7.93-7.76 (m, 3H), 7.63-7.43 (m, 3H), 5.87-5.67 (m, 1H), 5.21-5.06(m, 2H), 3.95-3.84 (m, 1H), 3.84-3.72 (m, 1H), 2.58 (ddt, J=13.8, 7.1,1.2 Hz, 1H), 2.33 (ddt, J=13.7, 7.6, 1.1 Hz, 1H), 2.12-1.89 (m, 3H),1.71 (ddt, J=10.9, 4.9, 4.3, 2.4 Hz, 1H), 1.34 (s, 3H); ¹³C NMR (126MHz, CDCl₃) δ 179.0, 175.3, 134.6, 133.7, 133.3, 132.5, 128.9, 128.1,127.7 (2C), 127.5, 126.4, 124.1, 118.9, 47.2, 44.0, 43.3, 33.3, 25.1,19.5; IR (Neat Film NaCl) 3059, 2938, 2869, 1677, 1467, 1383, 1293,1234, 1165, 1139, 923, 862, 822, 780, 762 cm⁻¹; HRMS (FAB) m/z calc'dfor C₂₀H₂₂NO₂ [M+H]⁺: 308.1650, found 308.1638; [α]D²⁵ −257.4° (c 0.92,CHCl₃, 97% ee).

Procedures for the Conversion of Benzoyl Lactam 3 to Various Derivatives

The benzoyl lactam 3 compound was converted to various derivatives viathe reactions described below (and depicted in Benzoyl Lactam 3 ReactionSchemes 1 and 2).

Piperidin-2-one 24

To a solution of lactam 3 (2.00 g, 7.37 mmol, 1.00 equiv) in MeOH (188mL) was added a solution of LiOH·H₂O (464 mg, 11.1 mmol, 1.50 equiv) inH₂O (75 mL). After 20 h, the reaction mixture was concentrated underreduced pressure and diluted with saturated aqueous NaHCO₃ (100 mL) andEtOAc (75 mL). The phases were separated, and the aqueous phase wasextracted with EtOAc (4×75 mL). The combined organic phases were washedwith brine (2×30 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The resulting oil was purified by flash chromatography(3×25 cm SiO₂, 40 to 60% EtOAc in hexanes) to afford known lactam 24 asa colorless oil (1.18 g, 96% yield). See Jakubec, et al., “Cyclic ImineNitro-Mannich/Lactamization Cascades: A Direct Stereoselective Synthesisof Multicyclic Piperidinone Derivatives,” Org. Lett. 10, 4267-4270(2008), the entire content of which is incorporated by reference.R_(f)=0.21 (50% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 6.05 (br s,1H), 5.88-5.66 (m, 1H), 5.12-4.95 (m, 2H), 3.25 (td, J=5.8, 1.9 Hz, 2H),2.48 (ddt, J=13.6, 6.7, 1.3 Hz, 1H), 2.18 (ddt, J=13.6, 8.1, 1.0 Hz,1H), 1.87-1.62 (m, 5H), 1.49 (dq, J=13.5, 7.4 Hz, 1H), 0.89 (t, J=7.5Hz, 3H); [a]D²⁵ −13.7° (c 0.57, CHCl₃, 99% ee).

Piperidine 25

To a solution of piperidin-2-one 24 (250 mg, 1.49 mmol, 1.00 equiv) inether (14.9 mL) was added lithium aluminum hydride (170 mg, 4.48 mmol,3.0 equiv) (Caution: Gas evolution and exotherm). After stirring atambient temperature for 5 min, the reaction mixture was heated to refluxfor 36 h, cooled (0° C.), and quenched with saturated aqueous K₂CO₃(20mL, Caution: Gas evolution and exotherm). The phases were separated, andthe aqueous phase was extracted with Et₂O (4×75 mL). The combinedorganic phases were washed with brine (2×30 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure to provide piperidine23 (206 mg, 90% yield) as a colorless oil. R_(f)=0.29 (20% MeOH in DCM);¹H NMR (500 MHz, CDCl₃) δ 5.76 (ddt, J=16.4, 10.6, 7.5 Hz, 1H),5.10-4.96 (m, 2H), 2.81-2.68 (m, 2H), 2.53 (dd, J=13.0, 20.0 Hz, 2H),2.06 (d, J=7.5 Hz, 2H), 2.02 (br s, 1H), 1.55-1.42 (m, 2H), 1.40-1.30(m, 2H), 1.32 (q, J=7.5 Hz, 2H), 0.80 (t, J=7.6 Hz, 3H); ¹³C NMR (126MHz, CDCl₃) δ 134.6, 116.9, 55.1, 47.0, 39.2, 34.9, 33.6, 27.7, 22.4,7.1; IR (Neat Film NaCl) 3298, 3073, 2963, 2931, 2853, 2799, 1638, 1462,1125, 996, 911 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₀H₂₀N [M+H]⁺:154.1590, found 154.1590; [α]D²⁵ −7.5° (c 0.80, MeOH, 96% ee).

Alcohol SI28

See Moss, et al., “Catalytic enantio- and diastereoselective alkylationswith cyclic sulfamidates,” Angew. Chem. Int. Ed. 49, 568-571 (2010), theentire content of which is incorporated by reference. To a vigorouslystirred mixture of benzoyl lactam 3 (291 mg, 1.07 mmol, 1.00 equiv) andNaIO₄ (915 mg, 4.28 mmol, 4.00 equiv) in CCl₄ (4.3 mL), MeCN (4.3 mL),and H₂O (6.5 mL) was added RuCl₃·H₂O (11.0 mg, 0.053 mmol, 0.05 equiv).After 28 h, the reaction mixture was diluted with half-saturated brine(30 mL) and extracted with DCM (5×25 mL). The combined organics werewashed with half-saturated brine, dried (Na₂SO₄), and concentrated underreduced pressure. The resulting residue was suspended in Et₂O (30 mL)and filtered through a pad of celite. The celite pad was washed withEt₂O (2×15 mL), and the combined filtrate was concentrated under reducedpressure. This crude residue was used in the next step without furtherpurification.

With cooling from a room temperature bath, the above residue wasdissolved in THF (19 mL) and then treated with lithium aluminum hydride(487 mg, 12.9 mmol, 12.0 equiv) (Caution: Gas evolution and exotherm).The reaction mixture was stirred at ambient temperature for 12 h andthen warmed to 40° C. for an addition 12 h. The reaction mixture wasthen cooled (0° C.) and dropwise treated with brine (20 mL, Caution: Gasevolution and exotherm). Once gas evolution had ceased the reactionmixture was diluted with half-saturated brine (20 mL) and EtOAc (20 mL).The phases were separated and the aqueous phase was extracted with EtOAc(5×50 mL). The combined organic phases were dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The resulting oil was purifiedby flash chromatography (3×12 cm SiO₂, 35 to 70% EtOAc in hexanes) toafford alcohol S128 as a colorless oil (162 mg, 61% yield for twosteps). R_(f)=0.36 (75% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.35-7.24 (m, 5H), 3.80-3.72 (m, 1H), 3.71-3.60 (m, 2H), 3.31 (br s,1H), 2.85-2.70 (br s, 2H), 2.00-1.70 (br s, 4H), 1.66-1.45 (m, 3H),1.35-1.10 (m, 3H), 0.81 (t, J=7.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ129.5, 128.4, 127.4, 63.9, 63.4, 59.4, 52.9, 39.9, 35.9, 35.1, 33.4,22.4, 7.5; IR (Neat Film NaCl) 3345 (br), 2933, 2793, 1453, 1350, 1115,1040, 1028, 739 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd for C₁₆H₂₆NO[M+H]⁺: 248.2009, found 248.2016.

Alcohol SI29

A mixture of alcohol SI28 (162.3 mg, 0.656 mmol, 1.00 equiv) and 20%Pd(OH)₂/C (50 mg) in MeOH (15 mL) was stirred under an H2 atmosphere for3.5 h. The reaction mixture was filtered through a pad of celite. Thecelite pad was washed with MeOH (2×15 mL), and the combined filtrate wasconcentrated under reduced pressure. This crude residue was used in thenext step without further purification.

To a solution of the above residue in THF (10 mL) was added Boc₂O (150mg, 0.689 mmol, 1.05 equiv). After stirring for 24 h, the reactionmixture was concentrated under reduced pressure and partitioned betweenDCM (20 mL) and saturated aqueous NaHCO₃ (20 mL). The organic layer wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresulting oil was purified by flash chromatography (2×20 cm SiO₂, 15 to35% EtOAc in hexanes) to afford alcohol SI29 as a colorless oil (130 mg,77% yield for two steps). R_(f)=0.34 (35% EtOAc in hexanes); ¹H NMR (500MHz, CDCl₃) δ 3.74-3.60 (m, 2H), 3.48 (br s, 1H), 3.31 (br s, 1H), 3.20(br s, 1H), 2.96 (br s, 1H), 2.16 (br s, 1H), 1.66-1.55 (m, 1H),1.55-1.42 (m, 3H), 1.44 (s, 9H), 1.40-1.27 (m, 2H), 1.25-1.15 (m, 1H),0.83 (t, J=7.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 155.2, 79.4, 58.7,52.5, 44.5, 36.1, 35.3, 34.6, 28.4, 27.6, 21.2, 7.4 ; IR (Neat FilmNaCl) 3439 (br), 2967, 2934, 2861, 1693, 1670, 1429, 1365, 1275, 1248,1162, 1045, 865, 767 cm⁻¹; HRMS (MM: ESI-APCI) m/z calc'd forC₁₄H₂₈NO₃[M+H]⁺: 258.2064, found 258.2069; [α]D²⁵ −7.0° (c 1.13, CHCl₃,96% ee).

TABLE 4 Methods for the Determination of Enantiomeric Excess for theabove Examples In the below Table, HPLC refers to high performanceliquid chromatography and SFC refers supercritical fluid chromatography.Also, ChiralPak and Chiralcel refer to the companies from which thecolumn resin (i.e., stationary phase) was obtained, and the letteringappearing after the company name refers to the specific material used.retention time retention time assay of major of minor entry productconditions isomer (min) isomer (min) % ee  1

HPLC Chiralpak AD-H 5% EtOH in hexanes isocratic, 1.0 mL/min 254 nm19.10 15.77 75  2

HPLC Chiralcel OJ-H 0.1% IPA in hexanes isocratic, 1.0 mL/min 220 nm15.22 18.10 81  3

HPLC Chiralcel OJ-H 3% EtOH in hexanes isocratic, 1.0 mL/min 220 nm18.68 17.60 86  4

HPLC Chiralcel OD 3% EtOH in hexanes isocratic, 1.0 mL/min 254 nm 28.8921.47 89  5

HPLC Chiralcel OJ 1% IPA in hexanes isocratic, 1.0 mL/min 254 nm 10.15 9.71 91  6

HPLC Chiralcel OD-H 3% IPA in hexanes isocratic, 1.0 mL/min 254 nm 15.7318.12 99  7

HPLC Chiralcel OJ-H 2% IPA in hexanes isocratic, 1.0 mL/min 254 nm 29.1219.74 99  8

HPLC Chiralcel OJ-H 5% IPA in hexanes isocratic, 1.0 mL/min 254 nm 32.9731.16 99  9

SFC Chiralcel OJ-H 3% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  3.85 2.49 99 10

SFC Chiralcel OD-H 10% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  3.84 3.20 99 11

HPLC Chiralpak AD-H 3% EtOH in hexane isocratic, 1.0 mL/min 254 nm 32.6927.83 99 12

SFC Chiralpak IC 10% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  2.67 3.84 99 13

HPLC Chiralcel OJ-H 3% IPA in hexane isocratic, 1.0 mL/min 254 nm  7.75 5.95 96 14

HPLC Chiralcel OJ-H 8% IPA in hexane isocratic, 1.0 mL/min 254 nm 25.9419.12 97 15

HPLC Chiralpak AD 2% IPA in hexane isocratic, 1.0 mL/min 254 nm 18.7227.05 95 16

SFC Chiralcel OJ-H 10% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  2.93 1.84 98 17

SFC Chiralcel OJ-H 5% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  2.31 3.73 93 18

SFC Chiralpak AD-H 15% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  4.16 5.05 99 19

HPLC Chiralcel OJ-H 5% IPA in hexane isocratic, 1.0 mL/min 254 nm 29.1624.82 93 20

SFC Chiralpak AD-H 10% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  1.96 1.41 99 21

SFC Chiralcel OJ-H 5% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  2.55 2.25 99 22

SFC Chiralcel OJ-H 3% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  3.05 2.72 94 23

SFC Chiralpak OJ-H 3% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  3.28 2.87 96 24

SFC Chiralpak AD-H 3% MeOH in CO₂ isocratic, 3.0 mL/min 235 nm  4.03 4.69 88 25

SFC Chiralcel OB-H 10% MeOH in CO₂ isocratic, 5.0 mL/min 210 nm  2.65 2.39 94 26

SFC Chiralpak AD-H 15% MeOH in CO₂ isocratic, 5.0 mL/min 210 nm  4.23 2.51 91 27

SFC Chiralcel OJ-H 10% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  4.53 3.80 99 28

SFC Chiralcel OB-H 10% MeOH in CO₂ isocratic, 5.0 mL/min 210 nm  4.05 4.60 99 29

SFC Chiralpak AD-H 20% MeOH in CO₂ isocratic, 5.0 mL/min 254 nm  3.73 2.93 97

Piperazinone Examples

Some exemplary piperazinone building blocks were prepared according tothe below reaction schemes.

Preparation of Piperazinone Building Block Compound 2

Piperazinone building block compound 2 was prepared according thefollowing Piperazinone Reaction Scheme 1 according to the followingreaction particulars.

According to the above Piperazinone Reaction Scheme 1, in anitrogen-filled glovebox, an oven-dried 2 dram vial was charged withPd₂dba₃ (21.3 mg, 0.023 mmol, 0.05 equiv), (S)—(CF₃)₃-t-Bu-PHOX (34.3mg, 0.058 mmol, 0.125 equiv), toluene (10 mL), and a magnetic stir bar.The vial was stirred at ambient glovebox temperature (˜28° C.) for 30min and 1 (182 mg, 0.464 mmol, 1.00 equiv) was added as a solution intoluene (5 mL). The vial was sealed and heated to 40° C. After 17 hours,complete consumption of the starting material was observed bycolorimetric change (from light green to red-orange) and confirmed bythin layer chromatography on SiO₂. The reaction mixture was removed fromthe glovebox, concentrated under reduced pressure, and purified by flashchromatography (SiO₂, 4:1 hexane:ethyl acetate) to afford piperazinone 2(145 mg, 0.413 mmol, 89% yield) as a pale yellow oil; ¹H NMR (500 MHz,CDCl₃) δ 7.57-7.55 (m, 2H), 7.50-7.47 (m, 1H), 7.42-7.26 (m, 7H),6.10-6.02 (m, 1H), 5.19-5.13 (m, 2H), 4.02 (d, J=13.5 Hz, 1H), 3.89-3.86(m, 1H), 3.62-3.57 (m, 1H), 3.42 (d, J=13.5 Hz, 1H), 2.91-2.79 (m, 3H),2.66-2.62 (m, 1H), 1.41 (s, 3H).

Preparation of Piperazinone Building Block Compound 4

Piperazinone building block compound 4 was prepared according thefollowing Piperazinone Reaction Scheme 2 according to the followingreaction particulars.

According to Piperazinone Reaction Scheme 2, in a nitrogen-filledglovebox, an oven-dried 2 dram vial was charged with Pd₂dba₃ (22.9 mg,0.025 mmol, 0.05 equiv), (S)—(CF₃)3-t-Bu-PHOX (37.0 mg, 0.063 mmol,0.125 equiv), toluene (10 mL), and a magnetic stir bar. The vial wasstirred at ambient glovebox temperature (˜28° C.) for 30 min and 3 (203mg, 0.50 mmol, 1.00 equiv) was added as a solution in toluene (5 mL).The vial was sealed and heated to 40° C. After 7 hours, completeconsumption of the starting material was observed by colorimetric change(from light green to red-orange) and confirmed by thin layerchromatography on SiO₂. The reaction mixture was removed from theglovebox, concentrated under reduced pressure, and purified by flashchromatography (SiO₂, 4:1 hexane:ethyl acetate) to afford piperazinone 4(161 mg, 0.445 mmol, 89% yield) as a pale yellow oil; ¹HMR (500 MHz,CDCl₃) δ 7.57-7.51 (m, 3H), 7.46-7.40 (m, 7H), 5.89-5.81 (m, 1H),5.26-5.18 (m, 2H), 4.16-4.12 (m, 1H), 3.82-3.69 (m, 2H), 3.63-3.50 (m,2H), 2.90-2.85 (m, 1H), 1.99 (s, 3H).

Preparation of Piperazinone Building Block Compound 6

Piperazinone building block compound 6 was prepared according thefollowing Piperazinone Reaction Scheme 3 according to the followingreaction particulars.

According to Piperazinone Reaction Scheme 3, in a nitrogen-filledglovebox, an oven-dried 2 dram vial was charged with Pd₂dba₃ (1.7 mg,0.002 mmol, 0.05 equiv), (S)—(CF₃)₃-t-Bu-PHOX (2.5 mg, 0.0047 mmol,0.125 equiv), toluene (0.5 mL), and a magnetic stir bar. The vial wasstirred at ambient glovebox temperature (-28° C.) for 30 min and 5 (15.5mg, 0.038 mmol, 1.00 equiv) was added as a solution in toluene (0.5 mL).The vial was sealed and heated to 40° C. After 18 hours, completeconsumption of the starting material was observed by colorimetric change(from light green to red-orange) and confirmed by thin layerchromatography on SiO₂. The reaction mixture was removed from theglovebox, concentrated under reduced pressure, and purified by flashchromatography (SiO₂, 4:1 hexane:ethyl acetate) to afford piperazinone 6(12.5 mg, 0.033 mmol, 87% yield) as a pale yellow oil; ¹H NMR (500 MHz,CDCl₃) δ 7.66-7.58 (m, 2H), 7.42-7.26 (m, 5H), 6.90-6.86 (m, 2H), 5.63(ddt, J=17.0, 10.3, 7.0 Hz, 1H), 5.19-5.12 (m, 2H), 4.02 (d, J=13.7 Hz,2H), 3.85 (s, 3H), 3.83-3.77 (m, 1H), 3.62-3.53 (m, 1H), 3.41 (d, J=13.7Hz, 2H), 2.91-2.79 (m, 3H), 2.66-2.59 (m 1H), 1.45 (s, 3H).

Additional Examples

Some additional building block compounds were prepared according to thebelow reaction schemes.

Preparation of Acyclic Building Block Compound 2

Acyclic building block compound 2 was prepared from acyclic substratecompound 1 according to the following Acyclic Reaction Scheme.

According to the Acyclic Reaction Scheme above, in a nitrogen-filledglovebox, an oven-dried 20 mL vial was charged with Pd₂pmdba₃ (27.4 mg,0.025 mmol, 0.05 equiv), (S)—(CF3)3-t-Bu-PHOX (37.0 mg, 0.0625 mmol,0.125 equiv), toluene (13 mL), and a magnetic stir bar. The vial wasstirred at ambient glovebox temperature (˜28° C.) for 30 min and 1(144.6 mg, 0.50 mmol, 1.00 equiv) was added as a solution in toluene (2mL). The vial was sealed and heated to 40° C. After 37 hours, completeconsumption of the starting material was observed by colorimetric change(from light green to red-orange) and confirmed by thin layerchromatography on SiO₂. The reaction mixture was removed from theglovebox, concentrated under reduced pressure, and purified by flashchromatography (SiO₂, 3×25 cm, 19:1→14:1→9:1 hexane:diethyl ether) toafford imide 2 (66.2 mg, 0.013 mmol, 53.9% yield) as a pale yellow oil;¹H NMR (500 MHz, CDCl₃) δ 7.68-7.52 (m, 3H), 7.52-7.43 (m, 2H), 5.70(ddt, J=17.2, 10.2 Hz, 1H), 2.28-2.18 (m, 1, 7.1 Hz, 1H), 5.09-4.97 (m,2H), 3.19 (s, 3H), 2.99 (tt, J=7.6, 6.0 Hz, 1H), 2.40 (dtt, J=13.9, 7.5,11H), 1.72 (dp, J=13.4, 7.5 Hz, 1H), 1.60-1.47 (m, 1H), 0.88 (t, J=7.4Hz, 3H).

Preparation of Lactone Building Block Compound 4

Lactone building block compound 4 was prepared from lactone substratecompound 3 according to the following Lactone Reaction Scheme.

According to the Lactone Reaction Scheme, above, in a nitrogen-filledglovebox, an oven-dried 20 mL vial was charged with Pd₂dba₃ (27.4 mg,0.025 mmol, 0.05 equiv), (S)-t-Bu-PHOX (24.2 mg, 0.0625 mmol, 0.125equiv), toluene (13 mL), and a magnetic stir bar. The vial was stirredat ambient glovebox temperature (˜28° C.) for 30 min and 3 (99.0 mg,0.50 mmol, 1.00 equiv) was added as a solution in toluene (2 mL). Thevial was sealed and heated to 40° C. After 30 hours, completeconsumption of the starting material was observed by colorimetric change(from light green to red-orange) and confirmed by thin layerchromatography on SiO₂. The reaction mixture was removed from theglovebox, concentrated under reduced pressure, and taken up in 10 mLTHF. The solution was cooled to 0° C. with an ice-water bath and LiBH₄(1.0 mL 2.0 M solution in THF, 2.0 mmol, 4 equiv) was added. After 30minutes stirring, an additional charge of LiBH4 1.0 mL 2.0 M solution inTHF, 2.0 mmol, 4 equiv) was added. After 40 additional minutes ofstirring, the ice-water bath was removed to allow the reaction to warmto room temperature (˜21 ° C.). After more hours stirring at roomtemperature, the reaction was complete as observed by thin layerchromatography on SiO₂. The reaction mixture was poured into a mixtureof water and ethyl acetate. A 1.0 M solution of HC1 in water was addedslowly. The aqueous phase was extracted five times with ethyl acetate.The combined organic layers were washed with brine and concentratedunder reduced pressure. The resulting crude product was purified byflash chromatography (SiO₂, 1.5×20 cm, 19:1 7:3 1:1 7:3 hexane:diethylether) to afford diol 4 (77.1 mg, 0.049 mmol, 97.4% yield) as a paleyellow oil; ¹H NMR (500 MHz, CDCl₃) δ 5.84 (ddt, J=16.4, 10.5, 7.5 Hz,1H), 5.11-5.02 (m, 2H), 4.12 (q, J=7.1 Hz, 1H), 3.69-3.51 (m, 2H), 3.37(d, J=0.8 Hz, 2H), 2.08-1.92 (m, 3H), 1.62-1.42 (m, 2H), 1.42-1.18 (m,2H), 0.86 (s, 3H).

Preparation of Imide Building Block Compound 6

Imide building block compound 6 was prepared from imide substratecompound 6 according to the following Imide Reaction Scheme.

According to the Imide Reaction Scheme, above, in a nitrogen-filledglovebox, an oven-dried 2 dram vial was charged with Pd₂pmdba₃ (5.0 mg,0.005 mmol, 0.05 equiv), (S)—(CF3)3-t-Bu-PHOX (7.7 mg, 0.013 mmol, 0.125equiv), toluene (3 mL), and a magnetic stir bar. The vial was stirred atambient glovebox temperature (˜28° C.) for 30 min and 5 (33 mg, 0.10mmol, 1.00 equiv) was added as a solution in toluene (0.3 mL). The vialwas sealed and heated to 40° C. After 5 days, complete consumption ofthe starting material was observed by colorimetric change (from lightgreen to red-orange) and confirmed by thin layer chromatography on SiO₂.The reaction mixture was removed from the glovebox, concentrated underreduced pressure, and purified by flash chromatography (SiO₂, 4:1hexane:ethyl acetate) to afford imide 6 (23 mg, 0.08 mmol, 80% yield) asa pale yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 7.55-7.47 (m, 2H), 7.36(dd, J=5.0, 2.0 Hz, 3H), 5.63 (ddt, J=17.3, 10.3, 7.4 Hz, 1H), 5.15-5.06(m, 2H), 4.99 (s, 2H), 2.80-2.65 (m, 2H), 2.45 (ddt, J=14.2, 7.0, 1.3Hz, 1H), 2.26 (ddt, J=14.0, 8.0, 1.1 Hz, 1H), 1.84-1.63 (m, 3H), 0.86(t, J=7.5 Hz, 3H).

While certain exemplary embodiments of the present invention have beenillustrated and described, those of ordinary skill in the art willunderstand that various modifications and changes can be made to thedescribed embodiments without departing from the spirit and scope of thepresent invention, as defined by the following claims.

1-30. (canceled)
 31. A method comprising treating a compound of Formula(III):

with a transition metal catalyst under alkylation conditions, therebypreparing a compound of Formula (IV):

wherein the compound of Formula (IV) comprises one of a (+) enantiomeror a (−) enantiomer in an enantiomeric excess of greater than 50%,wherein the transition metal catalyst is selected from Mo(CO)₆,Mo(MeCN)₃(CO)₃, W(CO)₆, W(MeCN)₃(CO)₃, [Ir(1,5-cyclooctadiene)Cl]₂,[Ir(1,5-cyclooctadiene)Cl]₂, [Ir(1,5-cyclooctadiene)Cl]₂, Rh(PPh₃)₃Cl,[Rh(1,5-cyclooctadiene)Cl]₂, Ru(pentamethylcyclopentadienyl)(MeCN)₃PF₆,Ni(1,5-cyclooctadiene)₂, Ni[P(OEt)₃]₄,tris(dibenzylideneacetone)dipalladium(0),tris(dibenzylideneacetone)dipall adium(0)-chloroform adduct,bis(4-methoxybenzylidene)acetone)dipalladium(0), Pd(OC(═O)CH₃)₂,Pd(3,5-dimethyoxy-dibenzylideneacetone)₂, PdCl₂(R²³CN)₂;PdCl₂(PR²⁴R²⁵R²⁶)₂; [Pd(η³-ally)Cl]₂; and Pd(PR²⁴R²⁵R²⁶)₄, wherein R²³,R²⁴, R²⁵, and R²⁶ are independently selected from H, alkyl, alkenyl,alkynyl, carbocycle, substituted hydrocarbyl, heteroatom-containinghydrocarbyl, and substituted heteroatom-containing hydrocarbyl,allylchloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium(II-),([2S,3S]-bis[diphenylphosphino]butane)(η³-allyl)palladium(II)perchlorate,[S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η-³-allyl)palladium(II) hexafluorophosphate, [Pd(S-tBu-PHOX)(allyl)]PF₆,and cyclopentadienyl(η³-allyl) palladium(II); wherein, as valence andstability permit, X is selected from —NR⁶— and —O—; Z is selected from—C(O)—and —CR⁷R⁷—; A is independently selected at each occurrence from—CR⁸R⁸— and —NR⁹—; W is absent or selected from —O—, —NR¹⁰—, and—CR¹¹R¹¹—; R¹ is selected from optionally substituted alkyl, alkenyl,alkynyl, carbocyclyl, heterocycle, aryl, heteroaryl, and halogen; R²,R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected at eachoccurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl,carbocyclylalkyl, and heterocyclylalkyl; R⁷, R⁸, and R¹¹ areindependently selected at each occurrence from hydrogen, halogen, nitro,alkyl, alkenyl, alkynyl, cyano, hydroxyl, thiol, carboxyl, sulfate,amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester,carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide,acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl,aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, andheterocyclylalkyl; wherein R⁷ and R⁸ may combine with the carbons towhich they are bound to form an optionally substituted 3-8-memberedring, R⁸ and R¹¹ may combine with the carbons to which they are bound toform an optionally substituted 3-8-membered ring, and when n is 2 or 3,R⁸ attached to one carbon may combine with R⁸ attached to another carbonto combine with the carbons to which they are bound to form a3-8-membered ring; R⁶, R⁹ and R¹⁰ are independently selected at eachoccurrence from hydrogen, hydroxyl and optionally substituted alkyl,alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl,heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl,aralkylcarbonyl, acyloxy, sulfone, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, and amide; and n is 0-3.
 32. The method of claim 31,wherein: X is —NR⁶—; A at each occurrence is —CR⁸R⁸— ; W is selectedfrom —NR¹⁰— and —CR¹¹R¹¹—; and n is 0-2.
 33. The method of claim 31,wherein: X is —O—, A at each occurrence is —CR⁸R⁸— ; W is selected from—NR¹⁰—, and —CR¹¹R¹¹—; and n is 0-2.
 34. The method of claim 31, whereinthe method further comprises a chiral ligand.
 35. The method of claim31, wherein a pharmaceutical product or a natural product is prepared.36. The method of claim 35, wherein the pharmaceutical product is a3,3-disubstituted pyrrolidinone, a 3,3-disubstituted piperidinone, or a3,3-disubstituted caprolactam.
 37. The method of claim 35, wherein thenatural product is (+)-quebrachamine.
 38. The method of claim 37,wherein the compound of Formula (IV) is


39. The method of claim 35, wherein the natural product is(+)-rhazinilam.
 40. The method of claim 39, wherein the compound ofFormula (IV) is


41. The method of claim 31, wherein the compound of Formula (IV) is

further comprising treating the compound of Formula (IV) with lithiumhydroxide in the presence of a solvent, thereby preparing the compound


42. The method of claim 31, wherein the compound of Formula (IV) is

further comprising treating the compound of Formula (IV) with lithiumaluminum hydride, in the presence of a solvent, thereby preparing thecompound


43. The method of claim 31, wherein the compound of Formula (IV) is

further comprising treating the compound of Formula (IV) with,successively, a) sodium periodate, carbon tetrachloride, acetonitrile,water, and ruthenium(III) chloride; and b) lithium aluminum hydride inthe presence of a solvent; thereby preparing the compound


44. The method of claim 43, further comprising treating the compound

with, successively, a) Pd(OH)₂/C in the presence of hydrogen and a firstsolvent; and b) Boc₂O in the presence of a second solvent; therebypreparing the compound